In the town of Ft. Chicken, Illinois, fourth grade student Shelly Linker eats a contaminated chicken nugget. Meanwhile, substitute teacher Clint Hadson arrives at Ft. Chicken Elementary, where he meets his high school crush Lucy McCormick, but discovers she is dating the PE teacher, Wade Johnson. At class, Clint is disrespected and ridiculed by his students.
During class, Shelly begins to succumb to the effects of the virus and attacks her classmate Patriot, as well as Clint, infecting them both. At recess, Shelly infects another child, Dink, who spreads the virus throughout the school. The infected children rampage on the playground, killing the staff. Police officer Dave arrives to quell the situation, but he is killed by Shelly.
The surviving staff members, consisting of Clint, Lucy, Wade, Doug, Rebekkah, and Tracy, hide in the music room with an uninfected student, Calvin. The staff discovers Clint has been infected by Shelly and quarantine him, but Clint only suffers mild illnesses. After rescuing an older student, Tamra, the staff is attacked by the infected students, forcing Wade to kill Dink. Wade, horrified by his actions, vents out his frustrations against Lucy, having noticed he and Clint's affections for each other. Meanwhile, Doug studies Dink's brain and concludes that the virus is only dangerous to the prepubescent, explaining why Clint and Tamra didn't turn feral.
Calvin passes out from diabetic shock. The school janitor, Mr. Hatachi, directs the staff to the ventilation systems, to which Clint opts to travel through them and retrieve a chocolate bar for Calvin. Lucy joins him, and the two confess their feelings for each other. Wade apologizes to the two for his earlier actions over a walky-talky. Clint and Lucy are attacked by the children, but they manage to secure a chocolate bar for Calvin, reviving him. The staff then battles the children on the playground and manage to escape in Wade's truck, but Wade is seemingly killed by the children.
The escapees are attacked by Patriot, who had stowed away on the truck, but he is killed by Clint. They then arrive in the nearby town of Danville, but discover that it has been overrun by the infected children. They discover that the virus has spread across North America, and are attacked by a horde of children. They hide in a funhouse, but the infected children, joined by Shelly, corner them. However, Wade and Mr. Hatachi arrive and rescue the group, setting the children aflame. They then escape with crossing guard Rick, driving out of the town.
- Elijah Wood as Clint Hadson.
- Alison Pill as Lucy McCormick.
- Rainn Wilson as Wade Johnson.
- Sunny May Allison as Shelly Linker.
- Armani Jackson as Calvin.
- Leigh Whannell as Doug.
- Morgan Lily as Tamra.
- Nasim Pedrad as Rebekkah Halverson.
- Jack McBrayer as Tracy.
- Jorge Garcia as Rick.
- Cooper Roth as Patriot.