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McGowan had her breakthrough in the horror film Scream (1996) and subsequently headlined the films Going All the Way (1997), Devil in the Flesh (1998), and Jawbreaker (1999). During the 2000s, she became known to television audiences for her role as Paige Matthews in The WB supernatural drama series Charmed (2001–2006). She starred in the double-feature film Grindhouse (2007), for which she was nominated for the Saturn Award for Best Supporting Actress.

In 2017, Time recognized McGowan as one of the Silence Breakers, the magazine's Person of the Year, for speaking out about sexual assault and harassment, specifically in regard to the Harvey Weinstein sexual abuse cases and the MeToo movement. In 2018, she released a memoir, Brave, and starred in the four-part documentary series Citizen Rose.