Lucas Nickle is a young boy who has recently moved into a neighborhood. Due to his lack of friends, he is constantly tormented by the neighborhood children, led by a boy named Steve. In anger, Lucas takes his frustration out on a colony of ants, squirting their anthill and flooding it with a hose. One day, his parents, Doreen and Fred, leave to Puerto Vallarta, leaving Lucas with his sister Tiffany and grandmother Mommo. The local exterminator, Stan Beals, arrives at Lucas' house and convinces him to sign a contract that will allow him to exterminate the ants, as well as the other insects living near Lucas' house.
An ant wizard, Zoc, decides to fight back against Lucas and creates a potion to shrink Lucas down to their size. That night, Zoc and a group of ants sneak into Lucas' house and pour the potion into his ear, causing him to shrink. The ants then abduct Lucas and take him into the anthill to stand trial for his actions. In spite of Zoc's insistence that the ants study Lucas and then eat him, he is overruled by the Queen, who sentences Lucas to hard labour. Zoc's girlfriend, Hova, offers to train Lucas, much to Zoc's objection. Though Lucas and Hova befriend each other, he is regarded with contempt by the other ants. During a foraging race for jelly beans held by an ant named Kreela and her husband, Fugax, Lucas costs his team the race. Humiliated, he leaves, followed by Hova. Soon afterwards, a swarm of wasps raid the ants, but Lucas scares them away with a firecracker, earning him the admiration of the other ants except for Zoc.
Lucas becomes sick after consuming honeydew, but he is cured by Hova. Hova introduces Lucas to the chamber of ages, where he is informed of the Great Ant Mother and the Cloud-Breather, whom Lucas recognizes as Stan Beals. Lucas sneaks into his house, along with Hova, Kreela and Fugax, and attempts to phone Stan to call of their contract, but is unsuccessful. Tiffany arrives soon afterwards and, upon noticing the ants, attacks them, injuring Fugax in the process, but they manage to escape in a drain. The group return to the anthill, where Zoc confronts Lucas and informs him that he will never restore him to his original size. Lucas leaves the anthill in despair, and is promptly attacked by a frog. Despite Hova's attempts to rescue him, Lucas is consumed by the frog. While inside the frog, Lucas meets a Beetle, a Glowworm, and a Fly. A remorseful Zoc soon afterwards allows himself to be eaten as well, but he then forces the frog to regurgitate him and the other captives, including Lucas.
Zoc and Lucas begin to bond afterwards and discuss their differences with each other. The next morning, Lucas sees Stan Beals arrive to exterminate the anthill. In order to stop him, Lucas and Zoc travel into wasp territory and propose a truce with their leader to help stop Stan. The wasps, upon seeing the damage being caused by Stan, agree to aid the ants. As Stan approaches the anthill, the wasps and ants attack him using the shrinking potion. However, Stan's headphones are inadvertently used as shields, and Stan easily overwhelms the insects with his pesticide. Lucas saves the lives of Hova and an injured wasp. As Stan prepares to destroy the anthill, the Beetle and Glowworm, who had travelled into his jeans, bite him in the groin, distracting him long enough for one of the wasps to inject him with the potion, misshaping him. A panicked Stan retreats using a stolen tricycle.
Lucas is hailed a hero for his actions, and Zoc gives him the enlarging potion that restores him to his original size just as his parents return from their trip. Shortly afterwards, Steve and his gang return, but Lucas stands up to Steve and rallies the other children against him to chase him away. Afterwards, Lucas rewards the ants with jelly beans.
- Zach Tyler Eisen as Lucas Nickle (known to the ants as Peanut The Destroyer).
- Julia Roberts as Hova, a nurse ant. Lucas' close friend and Zoc's girlfriend.
- Nicolas Cage as Zoc, a wizard ant. Hova's boyfriend and Lucas' rival friend but later good friend.
- Regina King as Kreela, a forager ant. Fugax's wife and Hova's best friend.
- Bruce Campbell as Fugax, a scout ant. Kreela's husband and Lucas' best friend.
- Ricardo Montalban as Head of Council.
- Paul Giamatti as Stan Beals.
- Lily Tomlin as Mommo, Lucas' grandmother.
- Allison Mack as Tiffany Nickle, Lucas' older sister.
- Cheri Oteri as Doreen Nickle, Lucas' mother.
- Larry Miller as Fred Nickle, Lucas' father.
- Myles Jeffrey as Steve.
- Jake T. Austin as Nicky.
- Meryl Streep as The Queen.
- Frank Welker as Spindle.
- Rob Paulsen as Beetle.
- S. Scott Bullock as Glow Worm.
- Mark DeCarlo as Fly.
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