Scream 22 takes place after Scream 21, Ghostface returns and someone needs to stop him.
- Keanu Reeves as Thomas Connor
- Georgie Henley as Hayley McDonald
- Neve Campbell as Sidney Prescott
- Matthew Lillard as Det Sam Macher
- Emma Bell as Fifi Mone
- Matthew Knight as Ethan Carsia
- Amber Heard as Jessica Mitchell
- Caroline D'Amore as Kristen Lovely
- A.J. Cook as Mary Polne
- Kyla Pratt as Erica Johnson
- Anthony Head as Mark Onie
- Debby Ryan as Tammy Wenser
- Bridgit Medler as Cammy Wenser
- Robert De Niro as Clark Wenser
- Bella Thorne as Lori Reed
- Matt Bennett as Sam Fixes
- Gage Golightly as Ursula Fixes
- Vincent Martella as Gary Time
- Thomas Conner
- Hayley McDonald
- Erica Johnson
- Ethan Carsia
- Jessica Mitchell
- Kristen Lovely-She doesn't know she's Ghostface, but when her ex-boyfriend, Mark, told her everything after he was unmasked, she's started to kill her own friends
- Mark Onie-He also had an affair with Maureen Prescott 25 years ago and he also became obsessed with her daughter Sidney a few years later.
- Gary Time-He is laying on on the sofa watching the Halloween remake when he is attacked and stabbed 15 times in the chest. (Kristen)
- Det Sam Macher-He is attacked in a parking lot he is stabbed in the back and the stomach. (Mark and Kristen)
- Ursula Fixes-She is tied up in a chair and has her throat slashed. (Kristen)
- Sam Fixes-He is also tied up in a chair he is stabbed in the forehead. (Mark)
- Lori Reed-Kirby Reed's sister, She starts a wild and violent fight with Fifi in the court house who during the fight gets a wooden chair breaks it picks up a leg and stabs her in the heart with it.
- Fifi Mone- She is shot by 2 police officers right after the fight ,she lays against the wall she lays against the wall and asks for God's forgiveness she then dies. (Mark)
- Clark Wenser-He is hit on the head with a hammer 4 times facturing his skull. (Kristen)
- Sidney Prescott-She is attacked and stabbed in the arm, hand and stomach then she is left for dead (Mark)
- Mary Polne-She is stabbed in both eyes then she has her face slashed. (Kristen)
- Tammy Wenser-She is attacked and killed in her car after leaving her father's funeral. (Mark)
- Cammy Wenser-She is also attacked and killed in her car after leaving her father's funeral. (Kristen)
- Kristen Lovely-She is attacked and stabbed in her chest by a mysterious figure in a Ghostface costume after her and Mark had unmasked when they got home.(Sidney)
- Mark Onie-He is shocked to see Sidney still alive, she says he didn't get the job done. She then says she always hated him because he claimed to be her father's best friend while he was blackmailing her mother to have an affair with him, because he caught her sleeping with Cottton Wearing.She shoots him with a gun she had when he grabs a gun from a desk drawer to shoot her.
Sidney still found it hard to believe that Sam Macher was gone they had become such good friends the last few years, he had wanted to make up for what Stu did and he did do that he also was a very good cop back home in Woodsboro and here in Maryland.She also was going to miss Fifi Mone she felt so sorry for her, the girl was very disturbed but she was also sincerly a sweet and nice girl.She went with Thomas Connor to her funeral for support he had been close to her and her family when she was younger and he was devasted by her death,also her friends were there to say goodbye to her.A few days later Sidney went out on a date with Thomas and they had a good time she was looking forward to finding out more about him.