Cotton Weary, now living in Los Angeles and the host of a successful talk television show, 100% Cotton, is contacted by Ghostface, who demands to know the whereabouts of Sidney Prescott. Cotton refuses to cooperate, and when Ghostface comes to his home, Cotton and his girlfriend Christine are murdered.

Detective Mark Kincaid contacts Gale Weathers to discuss the murders, prompting her to travel to Hollywood, where she finds Dewey Riley working as an adviser on the set of Stab 3, the third film in the series based on the Ghostface murders. Using a voice changer as a ruse, Ghostface kills Stab 3 actress Sarah Darling. Sidney, now 22, is living in seclusion as a crisis counselor for an abused women's hotline, fearing that another killer may strike. Having discovered Sidney's location, the killer begins taunting her by phone, forcing her out of hiding and drawing her to Hollywood. As the remaining Stab 3 cast, along with Dewey and Gale, gather at the home of Jennifer Jolie, Ghostface murders her bodyguard and uses a gas leak to cause an explosion, killing fellow actor Tom Prinze in the process.

Martha Meeks, the sister of Sidney's friend Randy, who was murdered while Sidney was in college, visits Sidney and the others to drop off a videotape that Randy had made before his death, posthumously warning them that the rules of a horror film do not apply to anyone in the third and final film of a horror trilogy and that any of them, including main character Sidney, could die.

Dewey, Gale, Jennifer, and the remaining Stab 3 cast, Angelina and Tyson, attend a birthday party for Stab 3's director Roman Bridger, where Ghostface strikes. Gale discovers Roman's dead body in the basement. Angelina wanders off alone before she is also murdered. Tyson attempts to fight Ghostface but the killer manages to throw him off a balcony to his death. Jennifer tries to escape through a secret passage, but Ghostface kills her as well. The killer then orders Sidney to the mansion to save Gale and Dewey, who are being held hostage. When she arrives, Ghostface forces Sidney to abandon her firearm and lures her inside where Gale and Dewey are bound and gagged with duct tape. As Sidney is untying them, Ghostface appears, though Sidney gains the upper hand using a second hidden gun to fight him off. Detective Kincaid shows up but is knocked unconscious by Ghostface. Sidney flees and hides in a secret screening room where she encounters Ghostface.

He reveals himself as Roman, having faked his death and survived being shot due to a bulletproof vest. Roman admits to being Sidney's half-brother, born to their mother Maureen Prescott when she was an actress in Hollywood. Four years ago, he had unsuccessfully tried reuniting with her. Bitter over the rejection, Roman would film all the men she philandered with. He showed Billy Loomis the footage of his father with Maureen, which motivated him to kill her, thus setting off the string of murders in Sidney's hometown and at her college. However, when he discovered how much fame Sidney had attracted due to those events, Roman snapped and lured Sidney out of hiding.

Roman then tells Sidney of his plan to frame her for the murders, before killing Stab producer John Milton. Sidney furiously tells Roman that he is responsible for all of the events that have occurred. A fight ensues between Sidney and Roman, which ends when Roman shoots Sidney in the chest. Sidney disappears, only to reappear and stab Roman in the back and chest. As he lies bleeding, Sidney shows him that she too was wearing a bulletproof vest. Dewey and Gale arrive when Roman suddenly resurfaces with a knife; unaware of his bulletproof vest, Dewey shoots him, but Sidney yells at him to shoot Roman in the head, which Dewey does, finally killing him.

Sometime after at Sidney's house, Dewey proposes to Gale, who accepts. Sidney returns from a walk with her dog and leaves her gates, which were previously shown to be alarmed, open. She enters her home and is invited to join Dewey, Gale, and Detective Kincaid to watch a movie. As she goes to join the others, her front door blows open behind her, but she walks away leaving it as is, finally confident that the murders are over.

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