In a Norwegian village, Helga Eveshim cautions her nine-year-old American grandson, Luke Eveshim, about witches. Real witches look ordinary and often seem friendly, but they kill children. Every country has its own "high witch," and the ruler of all is the Grand High Witch, creation’s most evil creature. Helga shows Luke the missing little finger on her left hand, a memento of a childhood encounter with a witch. Her neighbor, Erica Larsen, was snatched by a witch and never seen again, except inside a painting on her parents’ wall, where she grew older and eventually faded away. Telltale signs of witches are that they have a purplish tinge to their eyes and boxy feet with no toes. Also, being bald, they must wear wigs that often make them itch. Luke’s parents see him off to bed before they go out. The next morning, police arrive with the news that Luke’s parents were killed in an accident. Helga takes Luke to her other house in England. One day, a lady introduces herself and offers the boy a snake. Noticing her purplish eyes, Luke calls for his grandmother and the woman hurries away. For Luke’s birthday, Helga gives him a cage with two white mice that he names William and Mary. When Helga has fainting spells, a doctor suggests she stop eating sweets and take a vacation. Helga, Luke, and his mice travel to the seaside Excelsior Hotel. Miss Eva Ernst arrives moments behind them, accompanied by her secretary, Miss Irvine, and is greeted as a celebrity because she is the chairman of the fifth national convention of The Royal Society for the Prevention of Cruelty to Children. While exploring the hotel, Luke meets a heavyset boy named Bruno Jenkins, who nibbles on cakes in the lounge. The manager, Mr. Stringer, learns about Luke’s mice and confronts him, but Helga counters that she saw a rat in the corridor, and Luke adds that he saw a rat nibbling on cakes in the lounge. Mr. Stringer allows Luke’s mice to stay as long as they remain caged. In the lounge, Helga sees Miss Ernst and recognizes her from somewhere. Noticing that her tea and sandwich taste funny, she suspects something odd is happening and catches Miss Ernst watching her. Nearby, Bruno Jenkins sits with his parents, eating cakes, and Miss Ernst takes note of him, also. When Mr. Stringer finds signs of Bruno’s nibbling on several cakes, he orders his staff to place mousetraps around the hotel. Putting William and Mary in his pocket, Luke ventures into the convention hall where the Society is meeting. Hiding behind a screen near the stage, he sets up a tightrope for his mice. The door suddenly opens and Mr. Stringer leads Miss Ernst and over a hundred women into the room. As they sit down, Luke notices one woman’s purplish eyes. Another digs a scratching finger under her wig. Mr. Stringer is hustled out of the hall, and a woman locks the doors. As Miss Ernst takes the stage, women remove their shoes, revealing stubbed feet, and take off their wigs. Miss Ernst peels off her “face,” revealing the hideous features of the Grand High Witch. Decreeing that every English child must be “eliminated,” she orders the witches to return home, quit their jobs, and open chocolate shops with the money she will give them. On a prearranged day, they will offer free sweets for every child. The candy will be treated with her secret Formula 86, which will turn the children into mice two hours after they eat it. The Grand High Witch explains that she earlier put her formula on a bar of chocolate, gave it to a “repulsive” boy in the lobby, and promised him more if he came to the meeting hall at a designated time, two minutes from now. The witches hurriedly put on their shoes, wigs, and faces. Bruno Jenkins knocks and is ushered into the hall. Reaching the stage, he becomes sick and turns into a mouse. Luke runs for his life and is chased outside. Seeing a baby in a carriage, Miss Ernst pushes it down a hillside, but Luke stops it from going over a cliff. Going to his grandmother’s room, he finds her unconscious and Miss Ernst standing next to the bed. She informs Luke that Helga is an old adversary. Knocking the boy unconscious, she carries him back to the meeting hall, where the other witches await. She pours Formula 86 down Luke’s throat. Minutes later, he turns into a mouse. As the witches stomp, Luke scampers away through an airshaft. Still capable of speech, he greets Bruno behind the wall, along with William and Mary, but the real mice cannot talk. Luke and Bruno creep back into the meeting hall through the ventilation and find it empty. Seeing his father, Bruno wants to enlist his help, but Luke warns that his dad will stomp on him. To lure Bruno upstairs, Luke promises that his grandmother has peanuts for him. They ride the elevator and sneak along the sideboards, avoiding mousetraps. They slip into the maid's service wagon, but when she reaches for the towels, she pulls them out and screams. Another woman comes to the maid’s rescue, and as Helga opens the door to see what happened, she notices the helpful woman has purplish eyes. She shuts her door, but not before Luke and Bruno run into the room. When Luke speaks to his grandmother, she recognizes his voice. He introduces her to Bruno, declares that the Grand High Witch is in the hotel, and explains her evil plan. Luke hatches a scheme to steal the Grand High Witch’s formula from her room, located just below them, and sneak it into the witches’ food at the evening banquet. Helga lowers him to Miss Ernst’s balcony in a sock, and distracts the witch’s black cat with the dangling sock, while Luke slips inside. Exploring the room, he accidentally opens a book with little vials inside marked Formula 86. When Miss Ernst and Miss Irvine return, Luke wraps his tail around a bottle and drags it into hiding. Miss Ernst finds the cat on the balcony and looks up to see Helga dangling the sock. Helga apologizes for dropping her knitting on the balcony. Luke works his way upstairs and delivers the formula to Helga. It contains 500 doses. Helga puts Luke, Bruno, and the bottle in her handbag and goes downstairs. In the lounge she sits down with Mr. and Mrs. Jenkins and tries to explain that their son was turned into a mouse, but when she opens the handbag, Bruno’s mother becomes hysterical. In Miss Ernst’s room, the maid finds the open book with formula bottles inside, and dabs the liquid on her neck as if it were perfume. Downstairs, Mrs. Ernst berates Miss Irvine and orders her to go to her room and stay there. Angry over missing such an important event, the secretary quits and hurries away. Helga slips into the kitchen, drops Luke, and is ushered out by the kitchen staff. Hiding among potatoes, Luke avoids first a slicer and then a dip in boiling oil. He notices that one of the chefs has purplish eyes. Seeing that cress soup is on the menu, he climbs on a shelf and drops the opened bottle of Formula 86 into the soup. Meanwhile, the maid meets secretly with Mr. Stringer, but as he sniffs her neck, he recoils and hurries away. Looking in a mirror, the maid sees fur growing on her neck. When the cress soup is wheeled out as an appetizer for the banquet, Mr. Jenkins demands to be served some of it. The witch chef turns into a mouse in the kitchen and runs into the banquet room to warn Miss Ernst, but the witch stomps on her. As planned, Helga fakes a spill at her table, and Luke hides in the cleanup pan in the kitchen. Mr. Stringer carries the pan to Helga’s table, and as he stoops to clean the mess, she drops Luke into her purse. Noticing that Mr. Jenkins is about to eat the cress soup, Helga pushes the dish into his lap. When she opens her purse, Bruno says hello to his parents and Mrs. Jenkins passes out. Suddenly, the witches turn into mice, and the staff chases them around the room. Helga traps Miss Ernst by dropping a large glass over her. She alerts Mr. Stringer, who lifts the glass and chops little Miss Ernest in half with a cleaver. Helga hands Bruno to his parents. Luke and Bruno say farewell, and Bruno tries to cheer his parents as Helga and Luke leave. From her window, Miss Irvine watches Helga leave the hotel. Later, Miss Ernst’s trunk of money, Formula 86, and a list of all the witches in America arrives at Helga’s house. Helga is sad about Luke’s condition, but he assures her that he is happy to be a mouse. That night, Miss Irvine comes to the house and shoots a ray into Luke’s window, turning him back into a boy. His eyeglasses and the two white mice reappear. As Miss Irvine gets into her car, Luke yells to her to visit Bruno.