McGowan had some isolated acting appearances in the early 1990s, including small roles in a 1990 episode of the Fox TV series "True Colors" and the 1992 teen comedy "Encino Man". But her breakthrough came when Araki cast her as Amy Blue, the nihilistic speed freak of "The Doom Generation." In 1996, she had a supporting role in "Bio-Dome", was a mute femme fatale who hooks up with two escaped cons in "Lewis & Clark & George" and was involved in murder in L.A.'s underground scene in "Kiss & Tell." The petite actress also appeared in the 17-minute short "Seed,” as a hooker who was molested by her own mother.
After the phenomenal success of "Scream," one might expect McGowan to 'go Hollywood'; instead she continued to appear in independent films. She offered a cameo as one of a trio of Valley girls (alongside Shannen Doherty and Traci Lords) who are vaporized by a space alien in Araki's nihilistic look at Beverly Hills teenagers, "Nowhere" (1997). In "Phantoms" (1997), she and Joanna Going played sisters who return to their hometown only to find no one living there. McGowan won particular praise for her turn as a sexy young woman clad in a red strapless gown who romances Jeremy Davies in "Going All the Way" (also 1997).
In 1998 she played the self-destructive party girl sister of a young Boston man who has escaped his rough upbringing but finds himself being drawn back into a dangerous existence, and that year she played the orphaned high school student who, after an abusive upbringing by her grandmother and rejection from the teacher whom she seduces, turns homicidal in the uneven but bizarrely entertaining "Devil In the Flesh," which would become a stable of late-night pay cable programming. Next—as McGowan was building a niche portraying sexy, snarky bad/good girl teenagers—was another high school black comedy, "Jawbreaker" (1999), as the dictatorial leader of a tight-knit trio of high school hotties who unravel after accidentally killing a fellow student with the titular candy in a kidnapping scheme gone awry.
A string of more forgettable films followed, and for a period McGowan became more famous for her relationship with Goth rocker Marilyn Manson than her acting career, especially notorious was a red carpet appearance at the 1998 MTV Music Video Awards in which she came on Manson's arm wearing nothing but a completely see-thru fishnet sheath, a thong and heels that left very little to the imagination ("It was very photographed—hee-hee-hee," McGowan told E! Online. "I thought it was a hoot. I actually expected other people to be more crazy or flamboyant that night, and I wound up being kind of the only one."). The couple split in 2001, with McGowan citing his rock star lifestyle—including drug use—as the source of the relationship's demise.
After a turn in the oddball fantasy "Monkeybone" (2001), the actress shifted from features to television when she was cast in 2001 as lost sister Paige Matthews on The WB's popular witchcraft-themed series "Charmed" when one of the original actresses, Shannen Doherty, left the series after some behind-the-scenes squabbling. Though McGowan and her character were well-integrated into the popular but not-so-creatively-ambitious show, the actress always somehow gave the appearance that she was slumming. Meanwhile, she studied Ann-Margaret's moves in "Viva Las Vegas" when she signed on to play the actress opposite Jonathan Rhys Myers as the King of Rock ‘n’ Roll in the highly rated CBS miniseries "Elvis" (2005).
She returned to the big screen to costar in “The Black Dahlia” (2006), Brian De Palma’s take on James Ellroy’s complicated and richly-textured noir thriller about two hard-edged cops (Josh Hartnett and Aaron Eckhart) who descend into obsession, corruption and sexual degeneracy as they investigate the brutal murder of would-be actress Elizabeth Short (Mia Kirshner), who was found tortured and vivisected in a vacant lot in Los Angeles. Meanwhile, McGowan was cast in “Grind House” (2007), a pair of 90-minute horror films written and directed Robert Rodriguez and Quentin Tarantino. Rodriguez shot his segment, “Planet Terror,” in the first half of 2006, while Tarantino’s, “Death Proof,” began production that August. McGowan starred in both shorts.