Various flashbacks from subsequent episodes provide further insight into the relationship between Michael and his brother, and the reasons behind Michael's determination in helping Lincoln to escape his death sentence. In the episode flashbacks, the younger Michael is played by Dylan Minnette.
It is later revealed that Michael has Low Latent inhibition, a psychological condition in which the person sees the world as pieces, rather than mere objects. This allows Michael to create plans and make complex and very deliberate decisions rapidly.
After his father, Aldo Burrows, deserted the family, Michael took his mother's maiden name because she told him that his father was an alcoholic, which was later proved untrue. Following his mother's death that was caused by a brain aneurysm, Lincoln became his guardian and took care of him and prevented Michael from taking his own path into the life of crime. They both traveled in and out of different foster homes. Though they were usually kept together, there were times when circumstances required them to be placed separately. One instance occurred when Lincoln did a sentence in juvenile hall on assault charges when Michael was eleven. Michael was once placed with an abusive foster father, who was later killed by Aldo, where he rescued him, though the murder itself was never solved. When Michael would wake up in the mornings not knowing where his brother was, there would be an origami crane next to his bed, a sign his brother was watching out for him. In Niles North High School in Skokie, Illinois, Michael took an elective survey class in Arts and Crafts, which had a section to origami. He was immediately drawn to the precision and patience, which fascinated him to an extent that he began constructing a number of cranes out of any material he could find; a habit which continued into adulthood. He was a gifted student with an impeccable record and graduated magna cum laude with a Bachelor of Science and a Master of Science in Civil Engineering from Loyola University Chicago. Afterwards, he becomes a successful structural engineer at the architectural firm of Middleton, Maxwell & Schaum in downtown Chicago. The sixteenth episode of the series, "Brother's Keeper", reveals Michael and Lincoln's relationship three years before Lincoln was imprisoned at Fox River and the reason why Michael would go to such extreme lengths to save his brother from his death sentence. When Michael discovers that he has mistaken his brother's sacrifice for him, this prompts him to change his misconception in order to break Linc out from jail.
The opening scene of the series shows Michael's final preparation of his plan to infiltrate Fox River State Penitentiary; the tattooist is applying the finishing touches to Michael's tattoo, which is prominently featured in the first season. In order to get into Fox River, Michael stages a bank robbery, pleads no contest at his trial, and requests that he be sent to the prison nearest to his home. Michael begins his sentence on April 11, exactly a month before Lincoln is set to be executed. Once there, he scrutinizes every detail regarding the prison and its inhabitants.
Given Scofield's educational background, inmates and correctional officers alike would often wonder why a man of Michael's credentials would have thrown such a privileged life away to end up in a state penitentiary. What's even more intriguing is his weird "habits", as he is often seen conversing discreetly with his brother, Lincoln Burrows, both during Prison Industry time and Chapel time; and the fact that he tends to execute a highly defined stare around Fox River's boundaries immediately from the point he got incarcerated as well as being called personally on command by the prison's warden himself, Henry Pope.
The season follows Michael as he puts his plan into action while overcoming various obstacles. In the first 13 episodes, Michael is seen to have a specific objective in each episode that he must accomplish in order to build an escape route out of the prison. On the way, he recruits a number of people to aid in the escape: his cellmate Fernando Sucre (Amaury Nolasco) to help him dig, mob boss John Abruzzi (Peter Stormare) to get him on PI (Prison Industries) and provide air transport once they escape, and Charles Westmoreland (Muse Watson), who he believes to be D. B. Cooper and can help finance their lives as fugitives.
Michael feigns type 1 diabetes, giving him daily access to the infirmary (the escapees' exit point from the prison) and allowing him to build a relationship with Dr. Sara Tancredi (Sarah Wayne Callies), who happens to be the daughter of Frank Tancredi (John Heard), the Governor of Illinois. After agreeing to help Warden Henry Pope (Stacy Keach) finish his Taj Mahal replica in his office, Michael also forms a friendship with Pope. He also later stages "brief insanity" to gain access to the penitentiary's premises to gain contact with one of its insane inhabitants gifted with photographic memory, in order to re-acquire the portion of the tattooed blueprint that he lost after coming into contact with a steaming hot piece of metal.
Michael's relationship with Sara is featured prominently in the nineteenth episode, "The Key", where he fails to steal the key to the infirmary from her. Although she finds out about his motive for being in the infirmary in the following episode, Sara decides to help Michael by leaving the infirmary door unlocked on the night of the escape. Towards the end of the season, Michael finally succeeds in helping his brother escape from Fox River State Penitentiary, through the window of the infirmary in the nick of time, but also aids the escape of six other prisoners.
In the second season of the series, the story continues to follow Michael, his brother and other escapees as they try to evade the authorities pursuing them. Away from the prison setting, Michael and Lincoln are frequently featured in scenes together in the first seven episodes. Michael and Lincoln travel together, after the fugitives separate to accomplish each of their individual goals. When they fail to retrieve L. J. Burrows before his trial, they decide to head to Utah to find Westmoreland's hidden money. There, they reunite with the four of the other escapees: Sucre, C-Note (Rockmond Dunbar), T-Bag (Robert Knepper) and Tweener (Lane Garrison).
The seventh episode of the season, "Buried" marks the first time Lincoln and Michael separate, when Lincoln decides to go after his son, L. J., who has been released from prison. Michael fails to retrieve the money after being fooled by T-Bag. Nevertheless, Michael continues to execute his plan in order to meet the coyote at the 'Bolshoi Booze' location. Prior to leaving for 'Bolshoi Booze', Michael meets Sara at the location which he encoded in his messages to her inside the origami cranes. Thinking that she had declined his invitation to Panama, Michael goes to meet the coyote, who has the location of an escape plane to Mexico. There, Michael is reunited with Lincoln, Sucre and his father, Aldo Burrows (Anthony Denison).
When Aldo is killed by Agent Alexander Mahone (William Fichtner), Michael and Lincoln decide to confront "The Company" and the conspiracy, and bid farewell to Sucre, who alights the getaway plane to Mexico. After a brief capture by Mahone, Michael and Lincoln are aided in their escape by Paul Kellerman (Paul Adelstein), who turns against "The Company" in an act of self-preservation. Kellerman takes them to Terrence Steadman, the man Lincoln is accused of murdering. Steadman's suicide forces Michael, Lincoln and Kellerman to find Sara since she holds the key to unlocking information that can expose the conspiracy. After Sara joins them, Michael, Lincoln and Kellerman head to Chicago, where Sara's father has hidden the information. On the way, Sara tells Michael that she has fallen in love with him and later in the same episode Michael reveals that he feels the same.
With the help of the former Fox River warden Henry Pope, Michael and Sara succeed in getting the USB drive in Frank Tancredi's private locker. After leaving Kellerman behind, Lincoln, Michael and Sara soon found that the recorded conversation on the USB flash drive could not be used as evidence due to its modified time-stamp. They decide to blackmail Reynolds instead. When this also fails, Michael and Lincoln are forced to escape to Panama. Incidentally, they are also forced to leave Sara behind after she is arrested. Upon discovering that T-Bag is in Panama City, Michael decides to go and capture him, which he successfully does. However, when Michael returns his boat with Westmoreland's money to find Lincoln missing, he receives a call from Mahone, who demands the boat and the money in exchange for Lincoln's life. Michael outsmarts Mahone and escapes with Lincoln. At his new boat, Michael and Lincoln are reunited with Sara, who tells them that Lincoln has been exonerated after Kellerman's testimony.
Their happiness is short-lived when Agent Kim (Reggie Lee) arrives and threatens to kill Lincoln and take Michael to Sona, which causes Sara to shoot him. As the three flee from the scene with the police pursuing them, Michael and Sara separate from Lincoln and end up surrounded in a small isolated shack. After expressing their love for each other, they leave the shack. Unbeknownst to Sara, Michael confesses to Kim's killing and is arrested in her place. Michael is then imprisoned at the Penitenciaría Federal de Sona (Sona Federal Penitentiary). Michael is the fifth member of the Fox River Eight to be taken down by the authorities, and the second member not to die upon interception.
In the season premiere, Michael witnesses a brutal duel between inmates, the usual manner of settling disputes at Sona. He unintentionally makes an enemy of one of the most influential and powerful inmates at Sona, a drug lord named Lechero. Lincoln informs Michael that The Company needs him to break somebody out of Sona (James Whistler), and that they have taken Sara and LJ hostage to ensure his cooperation. He began to look for Whistler, only to find that he has a bounty on his head: whoever kills him can receive exoneration from the mayor of Panama City. As a result, Whistler had gone into hiding in the sewers. Eventually, he found him and successfully persuades Lechero to remove the bounty on his head.
With seven days to bust Whistler out of prison, Michael tried to take matters into his own hands and uses it to contact Sara and receive a coded message about her location. He relays this information to Linc, who unsuccessfully attempts to rescue Sara and LJ and gets Sara killed as a result (although later it is found that she really isn't, but they had her hidden). Michael then purposely short out the power, causing Lechero to call on Michael to fix it. Michael restores power to the prison and also manages to restore power to a previously broken electric fence. It is revealed that Michael fixed the fence so that the electricity will superheat a chemical that Sucre (who was hired as the new grave digger) sprays on it, as the heated chemical is able to melt steel.
Michael spies the Sona's guards but is seen by the second one, due to the lens glare. He observed that at 3:13 p.m., there would be a glare which causes one of the guards to look over to the other side. After a small raid takes place, the prisoners are rounded up in the yard. Captain Hurtado questions Michael to the point that he unholsters his pistol and puts it to Michael's head. Whistler manages to intervene on Michael's behalf. With the help of Mahone, Michael concluded that by drugging one of the guard's coffee, they could have that guard. As the escape plan continues Michael finally learns of Sara's death, which has a devastating impact on him. In a moment of weakness he seems to challenge Whistler to a duel death but this reveals to be only a diversion for the escape. The escape ultimately fails.
When the Company decided to rescue Whistler themselves, Michael foils their plans but he was suspected of such an operation. At the end of the episode he is being escorted out of SONA and is kept in solitary, being interrogated. He evenly relented and told them about Whistler, who then revealed that Gretchen Morgan is in charge of the operation. Later Michael finds out the officers that were with Gretchen have been killed. Michael and Whistler are returned to SONA. It was then when they turned to a new escape plan, with the help of Lechero, and that is through an underground tunnel.
Later in the tunnels with Mahone, Whistler and Lechero, he says they need braces to hold up the escape tunnel. Then, when part of the tunnel is about to fall, Michael puts a little piece of metal in to hold it up. Their escape plan was jeopardized with Sammy taking over SONA prison and investigating their escape, but Sammy was killed after the tunnel fell upon him. It is then revealed that Michael killed Sammy by taking out that little metal piece. McGrady joined the team in the escape. Later Michael, Whistler, Mahone, and McGrady escape from Sona, with Lechero, T-Bag and Bellick caught in the escape.
Michael successfully tricks Gretchen into giving LJ and Sofia back safely. When a shootout begins out a museum in Panama, Michael grabs the gun from Linc's car and has Gretchen in his sights, but she escapes when police start to shoot at her. Later on outside the hospital, LJ gave him the same origami rose that Michael had given to Sara on her birthday. Fueled by revenge, he bids farewell to his family as he goes on a solo mission to hunt down Gretchen.
In the season premiere, Michael has tracked down Gretchen and Whistler to Los Angeles as he prepares to avenge Sara's death. However, as he has Gretchen and Whistler at gunpoint, Gretchen reveals to him that she had lied about killing Sara. Unsure whether or not to believe her, Michael contacts Lincoln and then Bruce. When both Michael and Lincoln get arrested, Don Self tells them that they can either bring down the Company and get Scylla (A key card that stores every bit of information about The Company – essentially their "little black book") or go to jail. They refuse and are bailed out by Bruce. Bruce takes them to Sara where Michael and she joyfully reunite. However, a hired assassin named Wyatt eventually hunts them down and tries to assassinate them at Sara's safe house. It is then that Michael and everyone decide to take Self's offer. They are joined by Mahone, Sucre, and Bellick in their mission. To blend in with the crowds, Michael gets his tattoos removed via laser surgery. Throughout further episodes, Michael is seen to be experiencing health problems, getting nosebleeds and suddenly clutching his head in pain. He hides these from Lincoln and Sara, but in the episode "Safe and Sound" Michael experiences a bloody nose that he could not hide from Lincoln. Michael tells his brother "It's not a big deal." and Lincoln replies "It was a big deal when you were thirteen...". It appears that Michael's condition is one his mother also shared. During his mother's childhood, she also had frequent nosebleeds that stopped after a few months, but reappeared when she was older, shortly before she died at the age of 31 of a brain aneurysm (a discrepancy which was never directly explained when she turned out to be alive later in the season, however based on a statement by the General regarding prior results of a surgery, and later information revealed about Michael's mother, the explanation of the discrepancy is subtly implied). Michael is experiencing nosebleeds for the first time since 13 and is about to turn 31. In the episode "The Legend", Michael is no longer able to hide his sickness as he collapses in the warehouse. Sara takes Michael to the hospital where the doctors diagnoses him with a hypothalamic hamartoma, advising that surgery is required right away or else he might die.
Unwilling to go into surgery until they get Scylla, Michael receives temporary treatment from Sara and goes onwards with their plans to break into The Company. Although the group eventually succeeds in getting Scylla, Self betrays them and takes it for himself to try to sell it. Michael, however, had taken a small piece of Scylla and Self needs that piece to make Scylla complete. Self goes back to find Michael and shoots the warehouse and a gas tanker to try to force them out. Fortunately, Lincoln was not in the warehouse at the time, and upon discovering Self's car outside, he finds Self at the top of a building and knocks him unconscious. They bring Self in and are about to get Scylla when Gretchen holds the group at gunpoint, allowing Self and herself to escape. Everyone except Mahone head to the hotel Self and Gretchen are staying at. Michael tampers with the ladder outside so that when Self tries to escape, it comes loose and Self falls to the ground. Michael takes this opportunity to grab Scylla from an unconscious Self, but as he is running away his nose starts to bleed profusely. He begins losing his balance and blacks out, falling to the ground. Self then catches up and takes back Scylla. As he is preparing to shoot Michael, Company agents appear and start shooting at Self. Self jumps into Gretchen's van and they escape. The Company agents lift an unconscious Michael into their van and drive away, with Lincoln running after them.
Michael is then shown in a hospital bed, connected to many machines. A hand rests on his, and it is revealed that this is General Krantz. Lincoln visits The Company HQ and asks General Krantz to allow him to see his brother. The General leads Lincoln to Michael, assuring him that Michael is under the best medical care and that The Company's technology is years ahead of those currently provided to the general public. He also tells Lincoln that the only way they will operate and save Michael is if Lincoln brings Scylla back. In addition, General Krantz gives Lincoln a folder labeled "TOMBSTONE II", telling him that it is "added incentive." With Mahone arrested by Agent Lang and Agent Wheeler, it is now up to Lincoln, Sucre, and Sara to retrieve Scylla from Don Self and Gretchen and to save Michael.
With Sara by his side, Michael wakes up disoriented and weak. He asks her which hospital he is in, but Sara merely assures him he does not need to worry about it and that there are good doctors here to treat him. While Lincoln and Sucre go after Scylla, Sara stays with Michael and watches over him while he undergoes surgery. However, the procedure that the Company doctors use on Michael is nothing like anything Sara has seen before. General Krantz tells her that while the procedure is experimental, it has been used once before on a patient who ended up living a long and happy life. Because of the surgery, all of Michael's senses become active at the same time, causing him to have his life flash before his eyes. He suddenly sees himself back in his old cell at Fox River, with Charles Westmoreland greeting him. While conversing with Westmoreland and trying to figure out the truth behind Scylla in his subconscious, the Michael in surgery is dying and begins to flatline. The Company doctor injects an unknown serum into Michael as Sara panics and rushes to Michael's side, telling him not to give up. After finally realizing what Scylla really is and hearing Sara's voice, Michael wakes up.
Later on, Michael tells Sara that he had a dream about Scylla, and he explains that Scylla is not actually The Company's little black book, but knowledge regarding a chemical combination that can produce energy equivalent to that of the sun's. Lincoln visits Michael shortly after, who is shocked to find out that Lincoln is willing to work with The Company to retrieve Scylla. He attempts to convince Lincoln to stop what he is doing and that The Company cannot be trusted, but Lincoln gives Michael the "TOMBSTONE II" folder and reveals to him that their mother used to work for The Company before she died, and that he is just "following the family business." A preview after the season 4 finale shows Lincoln on the phone with Michael and says he will stop at nothing to get Scylla. Michael replies saying he will stop at nothing to stop Lincoln from succeeding.
Michael and Sara are seen exiting a pizza restaurant when a Company assassin tries to kill them. They escape. They then bribe a truck driver to let them hitchhike with him, fearing police. He calls Lincoln and tells him he will stop him from getting Scylla and reveals that their mother is alive. An undercover cop/company agent stops the truck and searches for Michael and Sara. He pretends he does not see anything and he murders the truck driver, telling Christina that he has them. Michael and Sara try to call Lincoln, but they lose the signal and the back lifter is stuck so they smash a vending machine to open the lift and they escape with the guy chasing after them. Michael kills him and takes a note from him asking who sent him. The guy's last words were, "Not Krantz." He then dies.
Michael and Sara stay at one of Sara's old friend, Deb, with whom she went to med school, who is out of town. Michael and Sara check the note they took from their abductor. It reads: I10R4AZMS=I-10 near route 4 in Arizona Michael Scofield. The back side reads B2348ROCKWELL1630VS, which they do not understand. Michael texts Lincoln to meet up with him, but instead Mahone comes. Mahone asks if Michael can explain his plan against the Company and Michael refuses to, since Mahone is working with the Company. Michael learns that Christina ordered their abductor to bring them to her, but not kill them. This provides greater incentive to Michael to want to take down the company. They head to Rockwell Avenue, where they find a car, gun, money,a cellphone and directions to a location they need to go. They head to an airport and check through a flight log list for the initials VS; they discover the name Vincent Sandisky. They abduct Sandisky and a car chase ensues. They are captured and Christina orders Michael and Sara to be killed. They are about to be executed, until the Company agents are killed by Lincoln, Mahone, and Self. Lincoln advises Michael to leave, but he refuses. Lincoln takes Sandisky with him as a hostage. Michael and Sara however, took Sandisky's cellphone which reveals he and Christina used to be lovers.
In the next episode, "S.O.B.", Michael calls Lincoln and informs him that Sandisky knows everything. Lincoln advises him to leave Miami, but Michael still refuses. Michael calls Christina and wants to meet with her to make an arrangement if he gets Scylla. She agrees, and, along with her men, heads to the warehouse where Michael and Sara are. They search the warehouse and Michael puts baggies filled with chemicals inside Christina's SUV and puts the air conditioning on, setting it to full. When Christina and her men return to the car, she starts it and when the heat hits the bags, the chemicals evaporate, suffocating the occupants. Michael and Sara take this opportunity to abduct Christina and tie her up and put her in the trunk. When she regains consciousness, and she reveals to Michael that Lincoln is not his brother. His real parents, who were Company agents, were killed. Aldo adopted Lincoln when he was three. She never loved Lincoln like she loved Michael. Michael says Lincoln was a brother more than she was a mother: She left, he stayed, he fed him, kept him off the streets and kept him in school. Christina does not want Michael to keep saving Lincoln. Michael demands to know where Lincoln is, and she does not answer until Michael attempts to torture her. She reveals the location at an Energy Conference. Michael leaves, leaving Sara to watch Christina. Michael meets Lincoln at the Energy Conference where the Indian Prime Minister's son, Navee Banjeeran, is assassinated by Christina's men. Lincoln and Michael reunite, whereby Michael reveals to Lincoln that Christina set them up. The police then pursue them. In the episode Vs. in season 4, it is revealed Sara is pregnant with Michael's child.
In the episode "Killing Your Number", Michael is forced to save Lincoln from the clutches of his mother, or save Sara from the clutches of the Company. He manages to save both and hands Scylla to Paul Kellerman. Michael is forced to try to kill his mother, but, when the gun misfires, Sara kills Christina, saving Michael.