18-year-old Drew Decker (Carmen Electra) receives a threatening phone call while home alone. Drew is chased outside by somebody dressed as Ghostface, who stabs her in the breast, removing one of her silicone implants. A vehicle driven by her father—who is distracted by getting a blowjob from his wife—hits her and she is murdered by Ghostface.
Cindy Campbell (Anna Faris) meets up with her boyfriend Bobby (Jon Abrahams) and her friends, Brenda (Regina Hall), Ray (Shawn Wayans), Greg (Lochlyn Munro) and Buffy (Shannon Elizabeth). Various news teams, including hack reporter Gail Hailstorm (Cheri Oteri), converge on the school in the wake of Drew’s murder. Gail hooks up with Buffy’s intellectually disabled brother Special Officer Doofy (Dave Sheridan), hoping to milk the facts out of him.
While Cindy is in class, she receives an ominous note and realizes Drew was murdered exactly one year after she and her friends accidentally killed a man. At a beauty pageant that evening, Greg is killed by the killer in plain view while the audience mistakes Buffy’s pleas for help as being part of her act of dramatic reading but Buffy wins the pageant, forgetting about Greg.
After Cindy goes home alone, the killer attacks her but retreats when Cindy contacts the police. Bobby arrives and is arrested after a knife and cellphone fall out of his pocket. As Cindy spends the night at Buffy and Doofy’s place, she receives a mocking call from the killer.
The following day, Bobby is released from jail. Buffy, is beheaded by the killer with a cleaver, though her severed head keeps talking and is eventually thrown out. That night, Ray and Brenda go to the movie theater to see Shakespeare in Love, where Ray is stabbed in the ear in a bathroom stall. The killer goes after Brenda but angry movie patrons, who are fed up with Brenda’s rude and obnoxious behavior, kill her by stabbing before the killer can.
Cindy throws a house party, hoping for safety in numbers. During the party, Bobby and Cindy go upstairs and have sex. Suddenly, the killer appears and stabs Bobby before disappearing. Cindy gets a gun from a drawer and Bobby follows. When Brenda’s stoner brother Shorty (Marlon Wayans) comes up from the basement, Bobby takes the gun and shoots him. Ray arrives on the scene, still alive.
Bobby and Ray confront Cindy in the kitchen and announce their intention to kill her and her father (Rick Ducommun), and that they are merely copying a real killer. Bobby admits being gay, while Ray denies being so. The plan backfires when Ray viciously stabs Bobby numerous times, angry because his favorite show, The Wayans Bros., has been canceled. The killer abruptly arrives and stabs Ray. He and Cindy fight, with Cindy employing moves copied from The Matrix and kicking him out a window. However, the killer vanishes before the police arrive.
At the police station, Cindy and the sheriff (Kurt Fuller) realize that Doofy is the killer and was faking his disability. Doofy has already escaped with Gail Hailstorm. Upon finding his discarded Ghostface mask in the street, Cindy begins screaming but is hit by a car, as the sheriff walks away.
In a mid-credits scene, Shorty is presumably giving advice on how to survive a horror movie but it is actually advice on how to successfully enact a robbery.