Luke's parents had been killed in a car crash. He ended up at the house of his grandma, Helga Eveshim. Helga took him in and told him stories of her youth of secretly hunting the witches, the demonic evil women who hurt and kill children all around the world. She told him about how her five friends were taken by the witches and that she lost a thumb to a witch. She also told him how to see a witch, which came in handy when a witch arrived and tried to give him a snake: he hid up the tree until she stormed away, displeased at having failed to get him.
Later on, Helga got diabetes (pneumonia in the film), and they went to a hotel. There, a strange woman named Eva Ernst also stayed. Luke was training his two mice, William and Mary, when Eva and a large group of other women arrived to have a meeting. He hid. Eva Ernst arrived on the stage and ordered the other women to remove their disguises. To Luke's horror, the women revealed themselves to be the witches of England. Eva Ernst took off her mask, revealing a hideously deformed face. He realized she was the Grand High Witch, the leader of the witches in the world that Helga had told him about.
The Grand High Witch revealed to the other witches her plan to use a potion to turn every child in England into a mouse so the adults will kill them. She demonstrated this by turning a boy named Bruno Jenkins into a mouse. One witch smelled Luke, alerting the other witches who chased Luke and caught him. They caught him and poured the potion into his mouth, turning him into a mouse as well. They tried to kill him, but he managed to escape. Luke then met up with Bruno and they made their way to Helga. Helga was horrified that her nephew had been turned into a mouse, but he calmed her down and told her their plan to defeat the witches. He snuck into the Grand High Witch's room and was able to steal a vial of the potion, as well as meeting three children who had been turned into frogs. He got out and met with Helga.
Luke told Helga he planned on putting the vial in the witches' soup, turning them into mice. As the witches went to the diner, he snuck into the kitchen and poured the potion into the soup. He got the tip of his tail chopped off by a chef, but he escaped. The witches ate the soup and turned into mice, and were then all hunted down and killed, including the Grand High Witch. He goes back home with Helga while Bruno reunites with his parents, despite being a mouse.
Luke has different fates in the book and movie after he destroys the witches in England.
- In the book, he and Bruno remain as a mouse, but he is happy as he is still loved by his grandma. They plan to capture the Grand High Witch's castle in Norway and use it to find and kill all the witches in the world.
- In the film, however, the Grand High Witch's former assisstant, Ann Irvine arrives and, having a change of heart, turns Luke back into a human boy and sets off to do the same to Bruno. She then gives them the names and addresses of the witches of America.