Scream 21 takes place after Scream 20, Fifi is taken to the hospital after she was found by the 2 teenagers and she is put in the same room as Hayley who is recovering from a broken leg, she suffered when she was fighting with Lauren who had attacked her, she stabbed Hayley in back and thought she had died but recently just found out she was still alive. Thomas was worried about Lauren is come for Hayley that is why there were police guards outside her hospital room. Can Thomas, Sidney, Hayley, Jessica, Ethan and Fifi stop Lauren as Ghostface this time.
- Keanu Reeves as Thomas Connor
- Georgie Henley as Hayley McDonald/Lauren Malloy
- Neve Campbell as Sidney Prescott
- Matthew Lillard as Det Sam Macher
- Emma Bell as Fifi Mone
- Meagan Tandy as Denisha Jansen
- Matthew Knight as Ethan Carsia
- Amber Heard as Jessica Mitchell
- Hart Turner as Tom Bennett
- Jennifer Carpenter as Alyssa Hendricks
- Tristen Wilds as Brian Olson
- Jessica Lowndes as Rebecca Paulsen
Lauren Malloy-She want to kill Hayley for revenge after she stabbed Hayley in fight
Det. Sam Macher
Rebecca Paulsen-Ghostface knocked her out a window and she fell 8 stories.
Brian Olson-Ghostface stabs him and chases him upstairs, then stabs him in the back on the stairs and hangs him.
Alyssa Hendricks-Ghostface stab her in the neck and then decapitated her with an axe.
Tom Bennett-Lauren unmasks herself and guts him in his bedroom.
Police Guards-An unmasked Lauren stabs them to death with a knife.
Denisha Jansen-An unmasked Lauren strangles Denisha with rope and hangs her.
Lauren Malloy-Hayley knocked Lauren unconscious and stabbed her in the chest.
An hour after Lauren went to the hospital, Sidney and Fifi planned to drive Thomas home. Before he left, he kissed Sidney on the lip and Fifi stared in shock. Thomas then leaves to go home.