One evening at Herrington High School in Ohio, a few teachers, the head football coach and the principal leave after discussions about the school's budget. Having left her keys behind, Principal Drake (Bebe Neuwirth) returns to retrieve them. In her office, she is barred from leaving by the Coach Willis (Robert Patrick) who becomes increasingly erratic, then impulsively stakes a pencil through her hand and Drake facially slashes Willis with keys. Drake flees to the main school doors only to find the handles chained up.
Just outside, is drama teacher Mrs. Olsen (Piper Laurie), but she is unable to assist Drake. Willis is then ambushed by Drake hiding in a room, smashing a jar on his head, seizes his keyset and grabs scissors for a weapon. Drake runs to the doors with Willis on her tail, unable to immediately find the correct key, allows Willis to get upclose and obstruct the door, but Drake successfully closes the padlock. Olsen then consecutively stabs Drake with the scissors, with an emotionless face, and reveals that Olsen is in cahoots with Willis.
The following morning, the film's protagonist students are introduced. Casey Connor (Elijah Wood), a dedicated but perpetually harassed and routinely bullied photographer for the school newspaper, is the unappreciated friend of Delilah Profitt (Jordana Brewster) (the paper's editor-in-chief and head cheerleader).
Delilah's boyfriend Stan Rosado (Shawn Hatosy) is contemplating quitting the school's football team to pursue more academic ambitions, to Delilah's disapproval. Zeke Tyler (Josh Hartnett), a student repeating his senior year who sells, among other illegal items, a powdery ecstasy-like drug he manufactures and distributes.
Zeke is confronted by Miss Elizabeth Burke (Famke Janssen), who expresses concern for him over his illegal activities.
Naive transfer student from Atlanta, Georgia; Marybeth Louise Hutchinson (Laura Harris), attempts to befriend self-styled outcast Stokely "Stokes" Mitchell (Clea DuVall), who deliberately confirms rumors of lesbianism even though she has a crush on Stan and is a fan of science-fiction novels. Marybeth, on the other hand, develops a crush on Zeke.
While eating lunch on the football field, Casey notices a strange creature on the field. He takes it to Professor Furlong (Jon Stewart), where the specimen is examined.
Furlong believes it to be a new species of cephalopod-specific parasite called a mesozoan.
Delilah takes Casey into the teacher's lounge to find a story for the front page, where they hide in a closet.
They witness the coach and the drama teacher assault the school nurse (Salma Hayek) by forcing one of the creatures into her ear. They also find the body of Mrs. Brummel (Susan Willis). Casey and Delilah flee, and Casey calls the police.
Principal Drake claims nothing is wrong and that Casey is seeking attention. The next day, Casey tells the others that he believes the teachers are being controlled by aliens and goes to show them the creature he found, which is gone. When confronting Professor Furlong about the creature, he becomes defensive and attempts to infect them.
Zeke cuts off Furlong's fingers and then injects his homemade drugs into Furlong's eye, seemingly killing him.
Concerned about Casey's suggestion that everyone at the school could potentially be infected, Zeke takes everyone he trusts to his house where he examines and experiments with Casey's specimen. He discovers that it needs water to survive and can be killed by his drugs because it is a diuretic. Zeke makes everyone take some of his drug to prove they are human and unaffected. Delilah is revealed as infected, and she destroys Zeke's lab and most of his drug supply before escaping.
Acting on Stokes' speculation that killing the queen alien would revert everyone to normal, the group returns to the school, where their football team is playing a game and infecting opposing players.
Believing Principal Drake to be the queen, they isolate her in the gym and fatally shoot her. Stan goes outside to see if it worked, but is infected by the coach. Zeke and Casey go to Zeke's car to retrieve more of Zeke's drugs. Casey leads infected students away from Zeke, who encounters Miss Burke in the parking lot and seemingly kills her when he makes his escape.
Casey returns to the gym, where Marybeth reveals herself to be the queen, having faked taking the test earlier. She attacks Stokes, who is stunned at the revelation. Casey and Stokes flee to the swimming pool where Stokes is injured and infected. Zeke and Casey go to the locker room, where Marybeth reverts to her human disguise, naked.
She explains that she is taking over Earth because her own planet is dying. Zeke is thrown into a locker and rendered unconscious. Casey takes the drug and tricks Marybeth into following him into the retracting bleachers. Casey traps Marybeth and stabs the drug into her eye, killing her.
One month later, everyone has returned to normal. Stan and Stokes begin dating, and Zeke takes Stan's place on the football team (while Miss Burke affectionately watches him practice). Casey begins dating Delilah and has become a local hero. Professor Furlong is adjusting to life with reduced eyesight and fewer fingers.