In his first appearance in "Simpsons Roasting on an Open Fire", Homer takes the small amount of Christmas money he made working as a Santa at the Springfield Mall and bets it at the dog track. Although Homer has inside information on which dog was going to win, he instead bets on the "long shot," Santa's Little Helper, believing the dog's name to be a sign. Santa's Little Helper finishes last, and his frustrated owner abandons him. Homer and Bart adopt Santa's Little Helper, and everyone is so happy that the family has a merry Christmas after all.
In various episodes, Santa's Little Helper can be seen chewing on newspaper and other objects in the Simpsons' household, tearing up the furniture, digging holes in the backyard and eating food from the dining room table. During the second-season episode "Bart's Dog Gets an F", Homer is fed up with the dog's rambunctiousnous and threatens to give away Santa's Little Helper unless he graduates from an obedience school.
In "Dog of Death", he nearly dies of gastric torsion (referred to in the show as a "twisting of the stomach") because Homer initially could not afford $750 for the required operation; in "Who Shot Mr. Burns? (Part One)", he breaks two legs when Bart's tree house is destroyed by Mr. Burns' oil well.
In the episode "The Canine Mutiny", Bart briefly abandons Santa's Little Helper for Laddie, a purebred and very well-trained collie he buys from a mail-order catalog. To do that, Bart uses a charge card he applied for under the name of his dog, yet the credit card company misread the form and issued a card to Mr. "Santos L. Halper". Laddie learns many tricks that Santa's Little Helper is completely unable to perform — most notably a back flip, CPR and using a toilet. The Simpson family nearly forgets about their old pet, and Bart eventually gives him away instead of Laddie when repo men take back everything he fraudulently purchased. Feeling guilty about this disloyalty and bored with his too perfect new dog, Bart tries to get Santa's Little Helper back. When he finally finds him, Santa's Little Helper is serving as a seeing-eye dog for a blind man, but eventually decides to return to Bart.
In the episode "Stop, Or My Dog Will Shoot!", he becomes a great hero after he saves Homer in a cornfield maze, and then becomes enrolled as a police dog, teamed up with Officer Lou. Lou and Santa's Little Helper make a good team, foiling crimes together. After biting Bart's left leg, Santa's Little Helper is sent off by the Simpson family to live with Lou. Later on, once Springfield Elementary is in danger and Bart isn't able to escape, Santa's Little Helper comes in to save him, and goes back to living with the Simpsons.
In season 14's "Old Yeller Belly", Santa's Little Helper leaves the Simpsons again when he is kicked out of the house by a furious Homer, who was angry at the dog for not rescuing him from a fire in the family's treehouse (Homer is rescued by Snowball V instead). Santa's Little Helper goes on to replace Duffman as the mascot for Duff Beer, but the Simpsons soon miss him terribly and enlist Duffman's help to get him back.
In Season 22's "How Munched is That Birdie in the Window?", after Santa's Little Helper devours Bart's pigeon, Raymond Bird, Bart gets mad at Santa's Little Helper and, unable to forgive him, the Simpsons are forced to gives him away to an ostrich farm, where Bart explains that Santa's Little Helper should never, ever devour a bird. However, after an ostrich turns against Bart, Santa's Little Helper refuses to help Bart, so Bart is forced to strangle the ostrich to death with his bare hands (Saying "WHY YOU LITTLE" in a very similar manner to his own father strangling him). Bart realizes the error of his ways and apologizes to Santa's Little Helper.
Santa's Little Helper sires 25 puppies with She's The Fastest in "Two Dozen and One Greyhounds". He sires another litter with Dr. Hibbert's poodle, Rosa Barks, in "Today I Am a Clown". There are at least 8 puppies in this litter; these puppies are given away to townspeople by the end of the episode.
The name "Santa's Little Helper" was chosen for the dog because Homer needed an "omen", said executive producer Al Jean, that would inspire him to bet on him at the dog track in "Simpsons Roasting on an Open Fire".
Frank Welker voiced Santa's Little Helper between 1991 and 2002, but has not appeared since "The Lastest Gun in the West". Dan Castellaneta (who has always voiced Santa's Little Helper for bit parts) provided the voice after Welker, who asked for a raise because the voices were hurting his throat, left the show.