As the movie begins, Sidney Prescott is on a book tour promoting her new self-help book, Out of Darkness. The book is based on her experience as a survivor of multiple Ghostface attacks in previous movies in the Scream series.
After her book tour, Sidney returns to her hometown of Woodsboro to stay with her aunt Kate. During her visit, Ghostface resurfaces and begins terrorizing the town again.
The current sheriff of Woodsboro, Dewey, and his wife Gale, a journalist, are also targeted by Ghostface. Dewey and Gale are now married and living in Woodsboro, but their relationship is strained. Dewey is still working as the sheriff, but he is struggling with health issues.
Sidney reconnects with her cousin Jill and her friends, including Kirby, Charlie, and Trevor. Jill is a high school student who is obsessed with horror movies, and her friends are all horror movie buffs as well.
As the killings continue, the town is thrown into chaos. The police struggle to keep the town safe, and everyone begins to suspect each other as the killer's identity remains a mystery.
As the body count rises, Sidney and her friends try to figure out who the killer is before it's too late. They discover that there are multiple people involved in the killings, all with different motives.
In the end, Sidney and her friends are able to identify the main killer and stop the murders. However, there are still unanswered questions, and the movie ends with the possibility of another sequel.