Cotton Weary, now living in Los Angeles and the host of a nationally syndicated television show, 100% Cotton, is called by Ghostface, who demands the whereabouts of Sidney Prescott, who has gone into hiding ever since the events of the second film three years ago. Cotton refuses to cooperate, and when Ghostface comes to his home, both 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 film within a film series based on the Ghostface murders. Using a voice changer as a ruse, Ghostface kills Stab 3 actress Sarah Darling.
Meanwhile, Sidney is now living in a secluded rural house as a crisis counselor for an abused women's hotline, as she is fearful that another killer may strike. Having discovered Sidney's number, 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 kills her bodyguard Steven Stone 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 attacked and murdered by Ghostface in the previous film, 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 movie franchise in the third and final film do not apply to anyone, and that any of them, including Sidney, could die.
Dewey, Gale, Jennifer, and the remaining Stab 3 actors, Angelina Tyler and Tyson Fox, attend a birthday party for Stab 3's director Roman Bridger, where Ghostface strikes. Gale discovers Roman's seemingly dead body, with a knife in his chest, in a movie-set coffin in the basement. Angelina, refusing to stick with Gale and Jennifer, wanders off alone before she is murdered. Tyson attempts to fight Ghostface but the killer manages to wound him. Then after a brief chase Ghostface throws him over the balcony killing him. Jennifer tries to escape through a secret passage, but Ghostface finds her and kills her as well. The killer then orders Sidney to the mansion to save Gale and Dewey's lives, as they are being held hostage. When she arrives, Ghostface forces Sidney to remove her firearm, which she does, and Ghostface lures her inside, as Gale and Dewey are bound and gagged. As Sidney is untying Gale and Dewey, Ghostface appears, though Sidney gains the upper hand using a second hidden gun to fight off Ghostface. Detective Kincaid shows up but is knocked out 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. 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 (setting off the events of Scream and Scream 2). However, when he discovered how much fame Sidney got because of those events, Roman snapped and lured Sidney out of hiding.
Roman then tells Sidney of his plan to frame her for the murders, and brings out John Milton, who was bound and gagged in a closet, killing him in front of Sidney. Sidney angrily tells Roman that all that has happened is because of his actions and that no one is to blame but him, to take responsibility for his consequences, a fight ensues between Sidney and Roman. Roman shoots Sidney in the chest, seemingly killing her. While preparing for Gale and Dewey to arrive, Roman is now surprised to see that Sidney's body disappeared. As he begins to place a call to Sidney's cellphone to locate her, he instead receives an incoming call from her. This distracts him long enough for Sidney to stab Roman in the back, and he falls. As he slowly dies, Sidney shows him that she too was wearing a bulletproof vest. She then plunges Roman's knife into his chest, apparently killing him. Dewey and Gale arrive, Gale surprised that Roman is the killer. Roman suddenly jumps up and tries to attacks them again, only for Dewey to kill him with a single gunshot to the head.
Some time after one morning, Dewey proposes to Gale, and she accepts. Sidney arrives back at her home. Sidney is invited to join Dewey, Gale, and Detective Kincaid to watch a movie. As she goes to join the others, a door behind her opens, but she walks away leaving it as is, finally confident that the murders have ended and she is now safe.
Output: Who is the Ghostface killer?