[10][12] McGowan had an untraditional childhood, living as a teenage runaway in Portland, Oregon and associating with a group of drag queens in the city.

McGowan next obtained the role of Tatum Riley in the slasher cult film Scream (1996), as the casting director believed she best embodied the "spunky", "cynical" but "innocent" nature of the ill-fated character.

[16] Amid her growing public profile, she was the cover model for the Henry Mancini tribute album Shots in the Dark, which was released in 1996, and became the face of American clothing company Bebe from 1998 to 1999.

McGowan spent the majority of the late 1990s headlining a variety of independent films, including roles in Nowhere (1997), where she reunited with Araki, as well as Southie (1996), Going All the Way (1997), Lewis and Clark and George (1997), and Devil in the Flesh (1998), where she usually played seductive and mysterious characters.

[23] In the dark comedy Jawbreaker (1999), she portrayed Courtney Shayne, a popular yet malevolent high school student who tries to cover up her involvement in a classmate's murder.

[24] To accompany the release of the film, Imperial Teen's music video for the song Yoo Hoo featured McGowan as her character harassing the band members with jawbreakers.

[25] Jawbreaker was a critical and commercial failure, but found success through home video release and subsequent television airings; it has developed a cult following.

In 2001, McGowan was cast for the role of Paige Matthews in the popular WB supernatural drama series Charmed, as a replacement for the lead actress Shannen Doherty, who had left the show.

In a review of the fourth season, Leigh H. Edwards of PopMatters added that the addition of Paige was "contrived and clunky", but welcomed the idea of McGowan joining the show as a witch "since she has major goth cred as Marilyn Manson's former flame".

[26] DVD Verdict's Cynthia Boris wrote that McGowan brought "a youthfulness" and "a fresh viewer perspective" to Charmed, further noting that "fans have come to enjoy her presence on the show.

McGowan starred alongside Brendan Fraser, Bridget Fonda, and Whoopi Goldberg in the dark fantasy comedy Monkeybone (2001) as a cat girl from a limbo-like carnival landscape where nightmares are entertainment.

She also appeared briefly as the roommate of the titular character in Brian De Palma's The Black Dahlia (2006), a film noir shot in Los Angeles and Bulgaria and opposite Josh Hartnett, Scarlett Johansson, Aaron Eckhart and Hilary Swank.

In Rodriguez's segment, Planet Terror, she starred as a go-go dancer and the leader of a group of rebels attempting to survive an onslaught of zombie-like creatures as they feud with a rogue military unit, while in Tarantino's segment, Death Proof, she played a brief role as a victim of a misogynistic, psychopathic stuntman who targets young women with his "death proof" stunt car.

[34] Her next film release, Fifty Dead Men Walking (2008), revolved around Martin McGartland, a British agent who went undercover into the Provisional Irish Republican Army (IRA).

This prompted director Kari Skogland and the film's producers to issue a public apology, stating that McGowan's views did not reflect their own.

[38] Also in 2008, McGowan took on a recurring role as a con artist on the acclaimed drama series Nip/Tuck, and co-hosted the TCM's film-series program The Essentials alongside Robert Osborne, discussing classic Hollywood film.

[39] In 2010, McGowan shot a cameo in the Robert Rodriguez feature Machete, a role ultimately cut, but included on the DVD release, and played a semi-homeless junkie in the fantasy drama Dead Awake.

[40][41] Roger Ebert described her role as a "piece of work", writing: "She has white pancake makeup, blood red lips, cute little facial tattoos and wickedly sharp metal talons on her fingers".

McGowan appeared in the Imperial Teen music video for "Yoo Hoo",[50] which was featured on the Jawbreaker soundtrack, and she recorded the theme song from the film Dead Awake (2010).

McGowan made her directorial debut with the short film Dawn, about a teen from a strict family who falls under the spell of a gas-station employee.

Dawn's salient literary and cultural references, paired with the film's high production value, gorgeous shots, its slow-burner buildup and gripping conclusion, bring something to the table for everyone, and portends an excellent directorial career for Ms.

[53] The independent Canadian horror film The Sound, released in 2017, starred McGowan as a best-selling author and paranormal investigator alongside Christopher Lloyd and Michael Eklund.

The piece was commissioned by UK's Heist Gallery, and was shown in 2018 at special screenings at the Institute of Light in East London on December 15 and 16, with proceeds going to the charity Refuge.

[69] In May 2014, McGowan held a defiant party in support of the Brunei-owned Beverly Hills Hotel, despite a boycott over Brunei's anti-gay laws, which prescribes death by stoning for same-sex activities.

"[80] In early January 2020, McGowan apologized to Iran in a tweet sent out in the hours after a US airstrike in Iraq killed Iranian Major General Qasem Soleimani.

In August 2020, McGowan criticized the Democratic Party for failing to "create change and provide support for citizens facing racial inequality, economic issues and police brutality".

[87] In the early 1990s, McGowan, then relatively unknown, was involved for two years with a man she refers to as William, who, she claims, kept buying her exercise equipment and fashion magazines in an effort to persuade her to get thinner.

[98] In January 2019, McGowan pleaded no contest to a misdemeanor drug charge in Virginia involving cocaine that was found in a wallet she left behind at Dulles International Airport in 2017.

[100] In October 2017, The New York Times reported that McGowan received a $100,000 settlement from film mogul Harvey Weinstein in relation to an alleged sexual assault in 1997.

[117][118] Payne responded to McGowan's allegation by writing a guest column in Deadline Hollywood; he acknowledged a consensual relationship stating that they had met at some point in 1991 (McGowan turned 18 in September 1991) at an audition for a comic short film that he was directing for the Playboy Channel and had no reason to believe she was under the age of consent as the part required an actress who was of age.