The film stars Neve Campbell, David Arquette and Courteney Cox Arquette, each reprising their roles from the first two films. This is the only part of the Scream trilogy not to be written by Kevin Williamson, as he was busy working on his short-lived television series Wasteland. Newcomer Ehren Kruger (writer of the film Arlington Road, who would later go on to write the highly successful screenplays for The Ring, The Ring Two and The Skeleton Key) was given the task of writing the script based on notes Williamson himself had sketched out.
Having experienced the trauma of the killings it Woodsboro and at Windsor College, Sidney Prescott (Neve Campbell) now lives in a secluded area of California where she works as a women's crisis counselor from her home. Her home has a security gate around it and she is now practically an agoraphobic, only leaving her house to walk her pet Golden Retriever. Her whereabouts are unknown even to her surviving friends (save for Dewey, played by Arquette, and her father.). Gale Weathers (Cox) has become a largely successful news reporter (of a sensationalist style), thanks to the books she wrote revolving around the murders of the first two films and subsequent films based on the books.
The film begins when Cotton Weary (Liev Schreiber), the man wrongly convicted of killing Sidney's mother prior to the first film, is murdered along with his girlfriend, Christine (Kelly Rutherford) for refusing to give up information about Sidney's whereabouts. Suspected of being related to the original killings, Los Angeles police detectives led by Mark Kincaid (Patrick Dempsey) inform Gale Weathers of Weary's murder, asking if she may know anything about a picture found at the murder scene. When she identifies it as a picture of Maureen Prescott, Sidney's mother, it becomes apparent the killings are linked to her murder.
Sidney, Gale and Dewey become involved in investigating. The cast and crew of the latest 'Stab' movie are systematically being killed off one by one, the actors in the order in which they die in the script. Sidney and her friends are also attacked. Even Roman Bridger, the movie director, is found stuffed in a trunk.
However, after the murder of John Milton (Lance Henriksen), a Hollywood produer, it turns out that Roman (who had faked his own murder) is the killer known as Ghostface, the connection being that he is Maureen's illegitimate son and Sidney's half-brother. It is further revealed that Roman is a product of rape, which occurred during Maureen's brief stint as a B-list movie actress in early 1970s. Roman tells Sidney that her mother left her father and cheated on him with Hank Loomis, causing Mrs. Loomis to leave her husband. Roman told Billy Loomis why his mother had left his father, and convinced him to kill Maureen. Roman also told Billy to have an accomplice who was weak and easily willing to help him out, which turned out to be Stu Macher. Roman's influence on the events in the second film is never explained. Eventually, when Sidney confronts Roman, she "kills" him by shooting him with a gun she sneaked in, but he was wearing a bullet-proof vest. He manages to shoot her in the heart, but she was also wearing a bullet-proof vest (one from the police station), and kills him. As per the "rules" of the horror movie, Roman, being the main villain, wasn't really dead and Dewey kills him for real after being told (by Sidney, the only one who knew of Roman's bulletproof vest) to shoot Roman in the head. Dewey's fast reactions are influenced by Randy's advice about the killer never dying immediately.
The film fast forwards to Sidney's secluded house in the woods. Dewey surprises Gale by asking her to sign a copy of her infamous book, The Woodsboro Murders. As Dewey has been openly honest about his feelings on the book (specifically in Scream 2), Gale is taken aback by his request but decides to sign it anyway. As she opens the front cover, a wedding ring is placed inside. Dewey asks Gale to marry him, even though they both agree that it may never work. However, they decide to give it a shot and Gale excitingly accepts. Sidney, who at the beginning of the film is seen ensuring that the gate to her home is secured and locked, decides to leave the gate open. As she walks through the door, she hesitates for a moment to activate the security alarm but ultimately decides not to. Detective Kincaid, still recovering from his injuries as he is seen wearing a cast, asks Sidney to join him, Dewey, and Gale for a movie. As Sidney walks away, the door blows open. Sidney walks away with the door left open as realizes her long-time fears have diminished and Sidney simply smirks at her new found freedom.
Most of the story is set in Hollywood, and focuses on the making of Stab 3, the Scream franchise's parody of itself. For instance, actors (Parker Posey and Matt Keeslar) are playing characters that are actors (Jennifer Jolie and Tom Prinze) playing characters based on Gale and Dewey respectively. There is a constant comparison between the "movie Gale" played by Jennifer and the "real" one.
"Jennifer Jolie" is a combination of Jennifer Aniston and Angelina Jolie. "Angelina Tyler" is a cominbation of Angelina Jolie and Liv Tyler. "Tom Prinze" is a combination of Tom Cruise and Freddie Prinze, Jr. "Tyson Fox" is probably derived from the names of Tyson Beckford and Jamie Foxx.
Jenny McCarthy's character of Sarah complains that she is playing a bit character that is killed off after two scenes. This is exactly what happens to Sarah, and the number of scenes she has in Scream 3.
The characters believe Randy's rules about surviving a trilogy, and by the end even Sidney herself believes she is in a trilogy. Several scenes take place on movie sets which are actually sets of the first film. The climax takes place in a producer's house, with various movie props and filming equipment figuring prominently. Finally, the movie literally ends with "the door being left open" for future installments.
Although, in the first few drafts, there was a fifth rule: "Never be alone" but was taken out because Gale immediately goes off alone afterwards.
Carrie Fisher plays Bianca Burnette, an employee of the studio making Stab 3. Talking with Gale, she says that when she was young she tried to win the casting to play Princess Leia, but the role went to a girl who slept with George Lucas.
The film had a sizeable opening weekend of over $34 million and it grossed $161 million worldwide.