NOTE: This spoiler was submitted by Jeremy

The film opens with the voice of the Hero (Chris Rock) telling a group of children watching a slideshow that witches are very real, and that they hate children. They are known for turning children into creatures, and that they must be stopped.

We then cut to when the Hero was a boy (here played by Jahzir Bruno). He lived with his mother and father until they tragically perished in a car accident. The Boy was sent to live with his Grandmother (Octavia Spencer) in Alabama. Although she tried her best to cheer him up, the Boy spent countless hours in his room mourning his parents. Soon, Grandma does manage to get the Boy eating and dancing with her again. The Boy even gets a small mouse that he keeps as a pet and calls Daisy. Everything seems fine until a mysterious woman watches them from outside, and Grandma catches a bad cough.

The Boy and Grandma go into town to the market one day. A woman named Zelda (Josette Simon) goes near the Boy and offers him a piece of candy while speaking in a raspy voice. A snake also crawls out of her sleeve. The Boy runs back to Grandma, whose cough has come back. Back home, the Boy explains to Grandma the type of woman he saw, and she confirms that this was no woman, but a witch. She knows how to spot them with how they talk and the way they dress. They wear long sleeves and gloves to cover their claws, heels to cover their hideously deformed feet, and wigs to cover their bald heads.

Grandma tells the Boy about when she was a child and knew a girl called Alice Blue (Ashanti Prince-Asafo). When they were playing together, Grandma saw Alice approach a woman offering her candy. Alice took it, and the next morning, she turned into a chicken. Although Grandma knew what happened, nobody believed her and they assumed Alice had run away. Grandma would visit Alice in her chicken pen every day, sad that she was never able to turn back to normal. Grandma then goes into a closet that she usually keeps locked, revealing a bunch of medicinal herbs and elixirs, and healing books.

The Boy and Grandma leave her home to get away to a hotel and bring Daisy along, though the Boy has to sneak her in since there are no pets allowed. A large group of witches, led by the Grand High Witch (Anne Hathaway), arrive at the hotel as well. The hotel manager, Mr. Stringer (Stanley Tucci), notices that she has her cat Hades with her and says there are no pets allowed, but he has no choice but to make an exception for her.

The Boy later meets an English child named Bruno Jenkins (Codie-Lei Eastick), who tells the Boy that he is supposed to meet a woman there who will give him candy. The Boy later sneaks into the room where the witches are meeting. The Grand High Witch commands them all to remove their disguises, revealing their hideous forms and monstrous teeth. She chastises them all for their lack of success recently, but she has concocted a special potion that will turn all children into mice. Bruno then enters right when she was expecting him, and she gives him the chocolate she promised him. Bruno then transforms into a mouse, which the Boy sees. As the witches begin trying to stomp on him, Daisy (voiced by Kristin Chenowith) speaks and tells the Boy that she will help Bruno. Daisy drags Bruno into the hiding spot, but it causes Grand High Witch to find the Boy, and she turns him into a mouse as well. She tries to get them by stretching her arms out through the vents, but the mice escape her and her claws get mangled when they hit the fan.

The three mice make their way back to the Boy’s room after narrowly avoiding being killed by the maid. They reveal themselves to Grandma, who is stunned to see her grandson as a mouse. Daisy reveals that she was a girl turned into a mouse a little over a year ago after running away from an orphanage, and her name was Mary. Grandma decides to look after the mice and keep them safe from the other humans who might try and exterminate them. She and the Boy come up with a plan to reverse-engineer an antidote to the potion that can turn them human again by stealing some of the Grand High Witch’s potion. Grandma places the Boy in a pouch and brings him down to grab a bottle, but the Grand High Witch almost catches them until Mr. Stringer interrupts and forces her to let them get away. Stringer brings Grand High Witch a cage for Hades, which the cat appears to enjoy.

Grandma gets one of her elixirs to use with the potion, but it doesn’t work since the potion doesn’t alter itself, meaning that there is no way for the mice to return to normal. Grandma is upset, but the Boy tells her he doesn’t have a problem with being a mouse, and Grandma agrees to love him, plus Bruno and Daisy, as her own.

The group then devises a plan to use the witches’ potion against all of them. The Boy sneaks through a vent with the potion and drops the whole bottle in a bowl of pea soup that the witches specifically ordered to be bland and flavorless. Grandma goes down to the dining hall and sees the witches as they gather for their meal. The Grand High Witch sees Grandma and appears to recognize her, taunting her with the fact that she was the one who cursed Alice when they were kids. Suddenly, the other witches begin to transform into rodents, causing the other hotel patrons to scream and try to stomp them out. Meanwhile, the mice steal the Grand High Witch’s room key (room 666, no less).

Grandma takes the mice to the room to steal the Grand High Witch’s stash of potions and money, but the villain encounters them first. She threatens Grandma and the mice, but Bruno and Daisy sneak under her bed, which is filled with mouse traps, and they use two to snap onto her feet. As the Grand High Witch screams in pain, the Boy launches himself and a whole potion bottle into the air, dropping the bottle down her throat and causing her to turn into a hideous rat. She chases the mice until Grandma traps her in a container stacked with books. She then goes to free Hades from his cage, leaving the cat to devour his former master. Grandma and the mice steal the potions and stash of money so that they can turn other witches into rodents.

Grandma tries to return Bruno to his parents, but they are disgusted at the sight of him being a mouse, so Grandma takes him in. She adopts him and Daisy, and while the Boy and Grandma know that they will most likely die together since a mouse won’t live for too long, they decide to make the most of their time together as a big happy family.

We go back to the Hero, now an older mouse, finishing his story to the children. He and Grandma have been recruiting other children to help fight back against witches, and the children appear excited and eager to do so. Grandma looks at the Hero and asks if he’s ready, to which he replies he has never been more ready in his life.

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In the late 1960's, a young Boy loses his parents in a car accident and stays with his Grandma. The two are soon haunted by the presence of witches, whom Grandma had encountered in her youth when the Grand High Witch turned her best friend into a chicken after giving her candy.

The Boy and Grandma go to a hotel to get away from the witches, only to find that the Grand High Witch has gathered a large coven there to get rid of children by turning them into mice. She demonstrates this on an English boy named Bruno, and it turns out the pet mouse Daisy that the Boy has kept was also formerly a girl that ran into the witches. The Boy is also turned into a mouse, so he must take the others to get help from Grandma. Although she tries to find a way to turn them back, the process turns out to be irreversible, but the Boy tells Grandma he is fine being a mouse.

The group then steals some of the Grand High Witch's potion and uses it to turn the rest of the coven into mice. When Grandma and the mice try to steal the rest of her stash, the evil witch tries to corner them until the mice cause her to drink her own potion, turning her into a rat. Grandma then sets the Grand High Witch's own cat Hades on her, leaving her to become cat food.

Grandma takes the mice in as her own and steals the Grand High Witch's money and potions to set across the world to defeat every last witch. In the present, the now older mouse and Grandma are recruiting other kids to help fight witches.