In Las Vegas, lonely 10-year-old, Lucas Nickle (Zach Tyler Eisen) is left with his older sister, Tiffany (Allison Mack), and his grandmother (Lily Tomlin) when his parents go to Puerto Vallarta. Neglected by his family and tormented by a local bully, Lucas takes out his frustration on an anthill and attacks it with a squirt gun, terrifying the ants. One ant, an eccentric wizard named Zoc (Nicolas Cage), tries to fight back. His girlfriend, a nurse ant named Hova (Julia Roberts), attempts to communicate with Lucas. She is almost crushed before being rescued by Zoc. The leaders of the colony use a potion to shrink Lucas down to ant size.
The local exterminator, Stan Beals (Paul Giamatti), convinces Lucas to sign a contract to kill vermin. Later, Zoc and a small troop of ants pour the potion onto his ear. He wakes up and discovers that he is now tiny, where he lands on a potato chip. He is carried to the anthill into a world of giant caves, caterpillars and ants. Zoc insists that Lucas should be studied then eaten, but he is overruled by the Queen (Meryl Streep). She sentences Lucas to hard labor.
Hova volunteers to train Lucas, much to Zoc’s mortification. They both learn about the differences between ants and humans. However, when she forces him to forage for jelly beans with Kreela (Regina King) and Fugax (Bruce Campbell) Lucas is unsuccessful. The ants are attacked by wasps. Lucas finds a discarded firecracker and uses it to scare away the wasps. This earns him the admiration of all the ants – except Zoc.