In the film, Arquette, 39, and Cox, 46, reprise their roles as Sheriff Dewey Riley and one-time newswoman Gale Weathers, now Riley's wife, who have to deal with the return of the killer Ghostface after a decade-long absence.
While Neve Campbell also returns from the first film, the rest of the cast are newbies, including Hayden Panettiere, Rory Culkin, and Emma Roberts.
Despite his personal struggles, returning to Scream and acting again with Cox was a rewarding and emotional experience for Arquette. "It was very cathartic for me going back to where it all started," the actor told PEOPLE in August. "In this industry, it doesn't happen a lot where you're involved in a project that spans 14 years. It's really been amazing."
Scream 4 opens in theaters on April 15. Look for the trailer to premiere on Entertainment Tonight on Thursday evening.
With reporting by MELODY CHIU