In 1968 Alabama, a young boy goes to live with his grandmother following the death of his parents in Chicago. Slowly, the boy gets cheered up with his grandmother, buying him a pet mouse whom he names Daisy. One day, Charlie goes to buy a box of nails to train Daisy and to build a house for her as well. The boy is approached by a witch trying to lure him with a snake and a caramel, but the grandmother calls him and the witch disappears.After telling the grandmother about the encounter, the boy learns that the witches are in fact real. She says a witch cursed her best friend Alice into spending the rest of her life as a chicken. The grandmother says that witches never leave once they find a child. Frantically, they decide to stay in a nearby hotel where her cousin Eston is the executive chef. While there, grandmother tells, the boy how to tell a witch from an ordinary woman: real witches have claws instead of fingernails which they hide by wearing gloves, are bald which they hide by wearing wigs that give them rashes, have square feet with no toes which they hide by wearing sensible shoes, have a purple tinge in their pupils and have a powerful sense of smell which they use to sniff out children.The next day, the boy takes Daisy and a rope to go get some training done at a grand hall. As he walks there, he meets a gluttonous but friendly boy named Bruno, who gets pulled away by his mother. He then goes into the grand hall, thinking that he will be alone. As he's getting ready to train Daisy, a group of witches led by their all-powerful leader, the Grand High Witch, go into the grand hall; the boy hides under the stage and discovers that the Grand High Witch is planning to give the world's children a potion, which will be used in confectionery products that can transform the children into mice. The Grand High Witch waits for Bruno to arrive, for whom she gave a chocolate bar previously laced with the potion. After Bruno arrives, he turns into a mouse and enters the vent where the boy and Daisy are hiding. The Grand High Witch forcibly transforms the boy into a mice before they escape.Fleeing to the hotel room where the boy and his grandmother are staying, they tell the grandmother of the witches' plan and discover that the Grand High Witch is staying in the hotel room below them and that Daisy was once an orphaned young human girl named Mary turned into a mouse by a witch. He, Bruno, and Mary devise a plan to get a bottle of the potion so that the grandmother can devise a cure to turn them back into children. The plan is successful, but since, she is unable to create a cure, they instead decide to put the potion into a broth of pea soup which will be given to the witches during their dinner. All the witches except the Grand High Witch, who realizes that she had met the grandmother before as she was the witch that turned Alice into a chicken, drink the soup. While the mice steal the Grand High Witch's room key, the witches all begin turning into rats and chaos ensues.After she and the mice flee to the Grand High Witch's room, the grandmother starts to collect all the potions to destroy them. The Grand High Witch finds the grandmother, and prepares to kill her but the mice intervene and trick the Grand High Witch into swallowing her own potion, transforming her into a rat. They trap her in an ice bucket and prevent her from escaping. Before they leave the room, the grandmother takes the Grand High Witch's trunk full of money and releases her cat Hades from its cage. As they close the door, Hades attacks and kills her. After Bruno's parents do not accept him, he joins Mary, the boy, and the grandmother to go home with the Grand High Witch's trunk and become a family. Years later, older boy and his grandmother advise young children against the witches.