Several years after the murder sprees that terrorized them in the town of Woodsboro and then again in a small college town, the survivors of those events have made attempts at getting on with their lives. Sidney Prescott (NEVE CAMPBELL), the target of those homicidal attacks, is now an anonymous crisis hotline operator. Gale Weathers (COURTENEY COX ARQUETTE) is a reporter for Total Entertainment, while the formerly, but wrongly accused Cotton Weary (LIEV SCHREIBER) has his own TV show.
Then there's Dewey Riley (DAVID ARQUETTE), a former cop who's now an advisor on the set of "Stab 3: Return to Woodsboro," the last installment of a horror trilogy based on that group's experiences. Although these people seem to have returned to as normal a life as possible, that changes when L.A. homicide detective Kincaid (PATRICK DEMPSEY) reports that the killings have begun again.
It seems that the killer is searching for Sidney and leaves photos of her dead mother at the crime scenes. As such, Gale and Sidney eventually join Dewey on the set of "Stab 3." There, they meet the film's director, Roman Bridger (SCOTT FOLEY), and producer, John Milton (LANCE HENRIKSEN), as well as stars Tyson Fox (DEON RICHMOND) and Sarah Darling (JENNY McCARTHY). They also meet their big screen counterparts, Jennifer Jolie (PARKER POSEY), who plays Gale, Angelina Tyler (EMILY MORTIMER) who plays Sidney, and Tom Prinze (MATT KEESLAR) who does the same for Dewey.
As Kincaid and the others, including bodyguard Steven Stone (PATRICK WARBURTON), try to protect Sidney and the performers, the survivors try to elude the killer while attempting to figure out his or her identity.