In 1996, the town of Woodsboro, California was terrorized by evil Ghostface killers Billy Loomis (Skeet Ulrich) and Stu Macher (Matthew Lillard). Stu hosted a party at his house, and after most of the guests left, Billy and Stu revealed to Sidney that they were both Ghostface. Billy and Stu were defeated by their main target Sidney Prescott (Neve Campbell). Sidney fought Stu and pushed a TV on his head, and then shot Billy in the forehead.

Years later, after five other Ghostface killers were also defeated by Sidney, a new Ghostface killer is terrorizing Woodsboro. One night, Tara Carpenter (Jenna Ortega) is texting her friend Amber Freeman (Mikey Madison), and suddenly Tara is attacked by the new Ghostface. Tara survives, the cops arrive and take her to the hospital. Tara's friends Chad Meeks-Martin (Mason Gooding), Mindy Meeks-Martin (Jasmin Savoy Brown), Liv McKenzie (Sonia Ammar), and Wes Hicks (Dylan Minnette), son of sheriff Judy Hicks (Marley Shelton), visit Tara in the hospital. Tara's sister Sam Carpenter (Melissa Barrera) and her boyfriend Richie Kirsch (Jack Quaid) are also there. Sam is the daughter of the late Billy Loomis, and has been having visions of Billy trying to convince her to become a killer just like he was.

It is revealed that the new killer is targeting people related to Billy and Stu. Sam and Richie convince Dewey Riley (David Arquette) to help them stop Ghostface. Sidney and Gale Weathers (Courteney Cox) also arrive to help them. After Ghostface kills Judy and Wes, Tara is attacked in the hospital, but is saved by Sam, Dewey, and Richie. Dewey is killed by Ghostface while the others escape. Sidney and Gale follow Sam, Tara, and Richie to Stu Macher's house, where Amber is hosting a party. Just like Stu's party was a trap, this party is also a trap. Most of the guests leave, and Ghostface kills Chad, as he and Mindy are related to the late Randy Meeks (Jamie Kennedy). Mindy is also attacked, but survives.

Amber is revealed to be the killer, and she kills Liv by shooting her in the forehead. Amber shoots Gale in the abdomen, and Sidney is forced to enter Stu's house once again. Richie reveals he is the other Ghostface killer, and he and Amber plan to frame Sam for the murders because she is Billy's daughter. Sidney, Gale, Sam, and Tara fight back against Amber and Richie. With a stove burner turned on, Sidney and Gale shoot Amber into the fire, burning her. Sam and Richie fight each other, just like Sidney and Billy did. Just as Richie prepares to kill Sam, Billy appears to Sam again to convince her to kill Richie. Sam listens to Billy and kills Richie. Amber is also killed after she comes back for one last scare. Sidney, Gale, Sam, Tara, and Mindy survive and are taken to a hospital, leaving Stu's house behind. Even though Billy and Stu were defeated years ago, their legacy lives on as other villains put on the Ghostface mask and costume.

Continuity mistake: In the scene outside the hospital, when Gale and Sidney try to make the protagonist reconsider her plan to leave, Courteney Cox's hair changes position in front of either shoulder several times between shots.

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