Teenager Drew Decker is home alone when she receives a phone call. The caller is persistent to find out her name, but she doesn't give in. The caller then reveals he is looking at her. Scared, Drew grabs a baseball bat and answers the front door (thinking it is the caller behind) and attacks a group of trick-or-treaters. The caller then appears in her house, dressed as Ghostface, and proceeds to chase her outside, where he rips her clothes off, which leaves her in white bra and thong. She runs into the sprinklers in her bikini; the killer catches up with her and stabs her in the breast and pulls out an implant. She runs along the road and sees her father, only to be run over by him while being distracted by her mother giving him fellatio. She is then murdered.
Cindy Campbell is on her computer when her boyfriend Bobby Prinze appears in the window. Bobby is upset because his relationship with Cindy "isn't going anywhere" (i.e., they have not slept together). Even though he expresses this to her, she refuses and Bobby leaves.
The next day in school, Cindy meets with Bobby and the rest of her friends, Brenda Meeks, Greg Phillipe, Ray Wilkins, and Buffy Gilmore. At the school, news teams are trying to interview the police and students who knew the girl who was killed the night before (her name is known as Drew Decker). The most prominent among the reporters is Gail Hailstorm, author of the recently released book You're Dead, I'm Rich. Cindy points out to the others that Drew's murder happened exactly one year after they accidentally killed a man during a night of drunk driving, and dumped his body off a pier. Greg swears the group to a pact that they will reveal what happened that night, and becomes physically abusive to Cindy when she exhibits reluctance.
One class, Cindy receives a note from someone telling her that they know about the incident with the man they killed. Cindy looks outside to see the killer waving at her.
After football practice, Ray and Greg are in the locker room with a bunch of other guys, and when Ray and everyone else leaves Greg for the showers ("Don't let Uncle Ray catch you!"), the latter goes off to the punching bag. After he finishes and take a shower, he finds a note tucked in the door of his locker showing a picture of his small penis. Enraged, he goes to Cindy and the others and tells them about the note, and is ridiculed for it.
Buffy, competing in a beauty pageant, does a dramatic acting piece during the talent portion. During her reading, Greg is murdered by the killer in the balcony. Seeing this, Buffy attempts to warn everyone, but her desperate pleas are taken by the audience and judges as an exceptional acting performance and Buffy stops caring about Greg when she won.
That night, Cindy is attacked by the killer, but she calls the cops and the killer escapes. Bobby shows up with the same gloves and knife as the killer, and is arrested. Cindy goes to stay with Buffy that night but receives a call from the real killer, which results in Bobby's release. Bobby and Cindy later bump into each other at school, but their reconciliation is awkward, stemming in part from Cindy not getting over Ginger Spice leaving the Spice Girls.
The killer confronts Buffy in the girls' locker room. Making a sarcastic, meta-fictional observation about horror movie clichés, Buffy mocks the killer, even as he stabs her, and continues to do so even after he decapitates her. In order to get her to really shut up, he throws her head in the lost and found bucket.
Ray and Brenda go to the movies to watch Shakespeare in Love. Ray, while in a bathroom stall, peeps in on another occupant, and is impaled through the head with a penis. The killer then attempts to kill Brenda in the auditorium, but because of her discourteous behavior, the other patrons kill her before he has a chance.
During a party at her house, Cindy has sex with Bobby. At the same time, the killer shows up at Shorty's house to kill him and his friends, but gets high on marijuana with them instead. When they are rapping with each other, the killer raps and kills everyone at the same time except for Shorty, who was beside him all the time. Shorty congratulates the killer for the rap.
At Cindy's house, the killer shows up and apparently stabs Bobby. As Cindy attempts to attend to Bobby's wound, Bobby shoots Shorty in the lung, causing marijuana smoke to exude. He reveals that the blood from his "wound" is ketchup, as he was never stabbed at all. Ray then appears, very much alive, and reveals that he and Bobby are copying the killer. When Cindy asks for a motive, Bobby points out that they don't need one, because horror movies like Scream do not boast logically coherent elements like plot or motive. Bobby also sarcastically suggests that it was lack of sex that drove him to do this, and reveals that he and Ray are gay lovers who will start a new life once they kill Cindy, a crime they will get away with because they are merely copycatting a real serial killer who actually exists. To conceal their guilt, they decide to stab one another in order so that the authorities will believe them to be victims of the real killer. As Ray stabs Bobby, Cindy yells "You guys are psychos! You've seen one too many TV shows!", only to have Ray respond angrily stabs Bobby to death while saying "Watching television shows doesn't create psycho killers - canceling TV shows does! The Wayans Brothers was a good show - and we didn't even get a final episode!" (thus breaking character, since the actor playing Ray is Shawn Wayans). However, the real killer appears shortly afterwards, stabbing Ray to death.
The killer then attacks Cindy, but after she repels him, he escapes. The police show up and take Cindy to the police station, where they find out that Buffy's brother Doofy (Dave Sheridan) was actually faking his mental retardation and is the real killer,(The Usual Suspects style) and is in cahoots with Gail Hailstorm. After Doofy and Gail escape, the sheriff and Cindy find Doofy's disguise in the street and as Cindy cries out in the street over this discovery, she is run over by a passing car, while the driver is getting fellatio.
During the end credits, two scenes are shown:
~ Shorty talking to the audience about his plans to rob a supermarket.
~ Doofy breaking up with his vacuum and making love with it.