Anita “Needy” Lesnicki (Amanda Seyfried), once an insecure teenager, is now a violent mental inmate who starts the story as a flashback while in solitary confinement. Needy and popular flag girl Jennifer Check (Megan Fox) have been best friends since childhood, despite having little in common. One night, Jennifer takes Needy to a local dive bar to attend a concert by indie rock band Low Shoulder. A suspicious fire engulfs the bar, killing several spectators, and Jennifer is taken by the band despite Needy's attempts to stop her. Later that evening, Jennifer, covered in blood, appears in Needy's kitchen and proceeds to eat food from the refrigerator. Unable to digest the matter, she vomits a trail of black, spiny fluid and then leaves in a hurry as Needy calls after her.

The next morning at school, Jennifer appears fine and shrugs off Needy's concerns. While the small town is devastated by the numerous deaths caused by the fire, Jennifer seduces the school's football captain, and then attacks him in the woods, naked, where his disemboweled corpse is later found. Meanwhile, Low Shoulder gains popularity due to their rumored heroism during the fire and offers to make a charity appearance at the school's spring formal.

A month later, Jennifer is beginning to look pale and accepts a date by school emo Colin (Kyle Gallner), only to brutally kill him that night. While Needy and her boyfriend, Chip (Johnny Simmons), engage in sex, Needy senses something dreadful has happened. She leaves in a panic and almost runs over Jennifer, covered in blood. She rushes home and finds Jennifer in her bedroom who initiates physical intimacy with her and soon explains what happened after the fire: Low Shoulder took her into the woods, and offered her as a virgin sacrifice to Satan in exchange for fame and fortune. However, although the sacrifice and greedy exchange were a success, Jennifer was not a virgin, and when the lead singer Nikolai (Adam Brody) murdered her, a demonic spirit took over her body.

The next day at school, as the town is stunned by Colin's death, Needy goes to the school library's occult section and surmises that Jennifer is a succubus; she is weakest when she is hungry, and must eat flesh in order to sustain her life and appearance. Needy tells Chip about her discoveries and warns him not to attend the dance. He does not believe her and she subsequently breaks up with him in order to protect him.

Chip goes to the dance, hoping to meet with Needy, but he is intercepted by Jennifer, who seduces him and takes him to an abandoned pool house. Needy arrives there and finds Jennifer feeding on Chip. Needy tries to drown Jennifer and then helps Chip out of the pool. Jennifer, hovering in the air, attacks Needy but is later stabbed by Chip with a pool skimmer. Jennifer escapes while Needy watches her boyfriend die.

Needy goes to Jennifer's home, crashes through the window and fights her with a Utility knife. Culminating with a stab to the heart, Needy finally destroys the demon and kills Jennifer. Jennifer's mother (Carrie Genzel) comes in and finds Needy with the utility knife on top of her daughter's body. Soon after, Needy is brought to an asylum. Since she was bitten by Jennifer, she has obtained some of Jennifer's supernatural powers. Set upon revenge for what was done to Jennifer and herself, she escapes the mental facility and hitchhikes a ride to the hotel where Low Shoulder is staying; she makes her way to their room and brutally murders them all.