Cotton Weary, now a prominent talk show host, receives a chilling call from the latest Ghostface, who demands to know the location of Sidney Prescott. When Cotton refuses to comply, Ghostface invades his home, brutally attacking his girlfriend, Christine. In a desperate rush, Cotton returns home, only to witness Ghostface murder Christine right before his eyes, followed by his own demise.
Meanwhile, Detective Mark Kincaid reaches out to Gale Weathers to discuss the alarming string of murders, which leads her to Hollywood. There, she finds Dewey Riley working as an adviser on the set of "Stab 3," the third installment inspired by the Ghostface killings. The tension escalates when Ghostface claims the life of actress Sarah Darling, forcing production to a halt. Amidst the chaos, the remaining cast, along with Dewey and Gale, gather at the home of Jennifer Jolie, the actress portraying Gale in "Stab 3." The horror intensifies as Ghostface murders Jennifer's bodyguard and orchestrates an explosion that claims the life of actor Tom Prinze.
Sidney, living in isolation while serving as a crisis counselor for an abused women's hotline, harbors a deep-seated fear of another attack. The killer, having discovered her whereabouts, taunts her with phone calls that mimic the voice of her deceased mother, Maureen Prescott. This manipulation ultimately draws Sidney out of her hiding place and back to Hollywood. Meanwhile, Martha Meeks, sister of Sidney's late friend Randy, delivers a vital videotape featuring Randy's ominous warning about the unique rules of a trilogy: anyone can die, including Sidney herself.
As the danger heightens, Sidney faces Ghostface at a movie set, prompting law enforcement to keep her under protective custody. The tension peaks when Dewey, Gale, Jennifer, and the rest of the cast—Angelina and Tyson—attend a birthday celebration for Stab 3's director, Roman Bridger. Gale's discovery of Roman's lifeless body in the basement leads to another Ghostface attack, resulting in the deaths of Angelina, Tyson, and Jennifer. Ghostface then lures Sidney to a mansion, promising to save Gale and Dewey. Upon arrival, Sidney is tasked with freeing them but is confronted by the killer. In a twist of fate, she manages to turn the tables, brandishing a concealed weapon in defense.
Detective Kincaid appears but falls victim to Ghostface, who is later revealed to be Roman—Sidney's estranged half-brother. Having faked his own demise and escaped a previous gunshot wound by utilizing a bulletproof vest, Roman harbors a deep resentment for being rejected by Maureen, their mother. He had initially sought reconciliation, yet his actions spiraled into darkness, leading to the infamous killings that haunted Sidney's life. As he explains his twisted reasoning, Roman attempts to eliminate Sidney while framing her for the murders. Following a ferocious battle, Sidney finds the strength to fight back with relentless resolve, ultimately stabbing Roman multiple times. When he resurfaces, armed with a knife and fueled by rage, Sidney implores Dewey to end Roman's violence once and for all. With a decisive shot, Dewey puts an end to Roman's reign of terror.
In the aftermath, Sidney returns home, where Dewey proposes to Gale, who joyfully accepts. As Sidney steps out for a brief stroll, she leaves her previously alarmed gates wide open. Upon her return, she is met with the unexpected invitation to join Dewey, Gale, and Kincaid for a movie night. However, an ominous gust blows her front door open, leaving Sidney unaware of the lingering shadows that still threaten her peace.
