After his parents are killed in a car crash, Luke Eveshim is taken under care by his grandmother, Helga. Helga tells Luke stories of witches, demonic women who torment and kill children, tipping him on how to defend himself. One day, a woman named Pamela harrasses Luke, and he realizes that she is a witch.
On Luke's birthday, Helga becomes ill with diabetes,prompting the two to stay at a hotel. At the hotel, Luke comes into comflict with the hotel manager, Mr. Stringer, due to keeping his pet mice at the hotel. Luke becomes suspicious of the Royal Society of the Prevention of Cruelty Children (RSPCC), who had arrived to hold an annual meeting at the hotel, and follows them into the balloom. Inside, Luke discovers that the RSPCC are actually all of England's witches, arriving for a meeting held by the Grand High Witch, the global ruler of all witches.
The chairwoman, Miss Eva Ernst, reveals herself to be the Grand High Witch. At the meeting, she presents to the other witches a formula to transform children into mice. She demonstrates this on another boy named Bruno Jenkins, who had eaten a chocolate bar laced with the formula. Bruno is transformed into a mouse and flees. During the end of the meeting, Luke is discovered and captured by the witches, who force-feed him the formula, transforming him into a mouse as well. The newly-transformed Luke meets Bruno and they return to Helga, devising a plan to stop the witches by feeding them their own formula.
Luke retrieves the Grand High Witch's formula from her room. Helga attempts to return Bruno to his parents, but they refuse to believe her claims that he has been turend into a mouse. Luke, with some difficulty, manages to douse the witches soup with the formula and escapes being killed by the staff. Helga finally manages to convince Bruno's parents of the situation as the witches eat the formula and are transformed into mice. As the staff begin slaying the transformed witches, the Grand High Witch accuses Helga and advances upon her. However, Bruno bites her and she transforms into a mouse as well. Mr. Stringer proceeds to kill the Grand High Witch.
After the incident, Luke and Helga return tot he countryside, Luke still a mouse. The two devise a plan to eradicate the witches throughout the world, Later that night, the Grand High Witch's assistant, Miss Irvine, who had escaped being turned into a mouse, arrives at Luke and Helga's house. Having repented her evil ways, Irvine returns Luke to human form and retusn his pet mice, and sets off to repeat the process with Bruno.