The talk show host said she and Cox "became so close" while filming the 1996 horror movie, which made it easier for her to seek advice.
"I remember at the poster shoot I was having a nervous breakdown because I was having a false sense of being pregnant," Barrymore recalled. "I kept asking you, 'How do you know if you're pregnant? We're supposed to shoot this poster, but oh my God, I just started dating somebody and how do you know?'"
Barrymore told her former costar that she "felt safe" confiding in her, calling Cox "the mature, safe person in the room" at the time.
"I was the older one and I was the right person to ask!" Cox quipped in response.
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The fifth installment of the Scream franchise hit theaters on Friday, nearly 25 years after the original film debuted.
Barrymore is now a mom to two daughters, Olive, 9, and Frankie, 7, whom she shares with ex-husband Will Kopelman. The star opened up to Queer Eye star Bobby Berk about the challenges of dating as a single mother during Thursday's episode of her eponymous talk show.
"I'm not there yet," she said about re-entering the dating scene. "I have two young girls and, like, I don't want to bring people home. ... I think it would take me a very long time to meet someone and get to know them before I could even ever introduce them to my daughters."
Berk, 40, assured Barrymore that "being careful" with her daughters "means you're a good mom."
"And I don't think anybody knows how to do anything, right?" Berk said. "So, don't put pressure on yourself because you don't know how to do it. I think going into it, saying to yourself, 'I don't know how to do it,' is the first step of figuring out how to do it."
He later added, "You're an amazing mother, don't question that at all.