Noelle and Cali Sheldon shared the role as the child of Jennifer Aniston and David Schwimmer's characters from 2003 until the sitcom's end a year later.
Now the pair, both 16, have been cast in Jordan Peele's thriller, Us.
In an Instagram post revealing the news on Tuesday, Noelle said they were both "so excited" at the opportunity.
The pair will appear alongside previously announced cast members including Winston Duke, Lupita Nyong'o and Elisabeth Moss.
The film is Peele's follow-up to the Oscar-winning satirical horror Get Out.
He described the movie only as "a new nightmare" when tweeting out its theatrical poster.
The tone of the film strikes a sharp contrast to the twins' appearances in Friends - which famously saw Rachel sing "I like big butts" in an effort to keep baby Emma from crying.
The girls are not only sisters, but also "best friends".
"Happy 16th birthday to my #1, my fav and my built in best friend," Noelle said last month.
"Cali, you are my soul mate and I'm so lucky to have you as my bestie! Love you so much and so excited for a lifetime of adventures with you."