Subsequent credits included Husbands and Wives (1992), Kalifornia, What's Eating Gilbert Grape (both 1993), Natural Born Killers (1994), Strange Days (1995) and From Dusk till Dawn (1996).

Lewis received an Emmy Award nomination for the television film Hysterical Blindness (2002), and went on to co-star in the mainstream features Enough (2002), Cold Creek Manor, Old School (both 2003) and Starsky & Hutch (2004).

Lewis has worked more frequently in television since the mid 2010s, appearing in major roles on series such as Wayward Pines (2015), Secrets and Lies (2015–2016), Queer as Folk, Welcome to Chippendales (both 2022) and Yellowjackets (2021–2023).

[12] Lewis had a minor part in the science fiction comedy My Stepmother Is an Alien (1988)—playing Lexie, the best friend of main character Jessie—before landing her first major supporting role as Audrey Griswold in National Lampoon's Christmas Vacation (1989),[13] which is now regarded as a "classic" in its genre.

[16] In 1990, Lewis co-starred with Brad Pitt, whom she would go on to date for four years,[17] in the Lifetime television film Too Young to Die?, a crime drama based loosely on the case of Attina Marie Cannaday.

[18] In his review for the Los Angeles Times, Ray Loynd felt that the film worked due to its "compelling script [and Lewis'] authentic portrayal of the young and abused murderess whose first question to her public defender [is] whether he has any sugar-coated candies".

[19] Lewis garnered international attention when she beat out 500 other actresses to play Danielle Bowden,[20] the daughter of a family targeted by psychopathic criminal Max Cady, in Martin Scorsese's 1991 remake of Cape Fear (1962).

[27] In 1992, Lewis had a supporting role in Woody Allen's Husbands and Wives, with Rita Kempley of The Washington Post describing her portrayal of Rain—a "Lolita"-esque college student— as "sumptuous".

[32] Next, she appeared as a psychiatric patient in the music video for Melissa Etheridge's "Come to My Window",[33] and starred in the Lasse Hallström-directed What's Eating Gilbert Grape (also 1993), playing Becky, a free-spirited drifter who befriends a young man and his disabled brother in a small Midwestern town.

[40] She then starred as rock singer Faith Justin in Kathryn Bigelow's experimental science fiction film Strange Days (1995), doing her own singing on covers of two songs written by PJ Harvey.

In 1996, Lewis had supporting roles in comedy-drama The Evening Star—a sequel to Terms of Endearment (1983)—and the Quentin Tarantino/Robert Rodriguez action horror film From Dusk till Dawn.

The film received largely unfavorable reviews,[46] though Stephen Holden of The New York Times felt that it was "beautifully acted", noting, "Carla is played by Ms. Lewis with enormous heart and sensitivity, and with body language so precise that you soon forget it is a performance".

The latter received unfavorable reviews, with A. O. Scott of The New York Times writing that Lewis and co-star Lili Taylor "overact like second-string sketch performers on Saturday Night Live".

[60] That same year, she featured as a guest vocalist on The Prodigy's album Always Outnumbered, Never Outgunned,[61] played the supporting role of Kitty in the big-budget action comedy Starsky & Hutch,[62] and headlined Blueberry, a French acid Western directed by Jan Kounen.

[66] The band toured internationally in support of the album, receiving a favorable concert review from The Guardian's David Peschek, who wrote that Lewis is "exactly the kind of iconic presence that boringly boy-saturated rock needs".

[69] Next, she played a key role in Drew Barrymore's directorial debut, the 2009 comedy-drama Whip It!,[70] and provided voice work for the animated science fiction film Metropia (also 2009), directed by Tarik Saleh.

[75] She also portrayed a murder witness in the biographical crime drama Conviction,[76] with The Wall Street Journal calling her a "scene-stealer",[76] and the Boston Society of Film Critics awarding her Best Supporting Actress.

[82] A tragicomedy based on the Tracy Letts play of the same name, the film was met with mixed reviews,[83] but critics singled out Lewis as one of its strengths, with SFGate's Mick LaSalle feeling that her portrayal of youngest sibling Karen was the only performance to have "a complete grasp of the material's proper tone".

The show received a mixed reception, with Neil Genzlinger commenting in his review for The New York Times, "Ms. Lewis's dour detective character, Andrea Cornell, is a cliché stretched beyond the point of believability".

[93] Next, she had a recurring guest role on the first season of the science fiction mystery series Wayward Pines (2015),[94] contributed vocals to the song "Stickup" by Karma Fields and Morten,[95] and played the mother of a high schooler in techno-thriller Nerve (2016).

[97] She guest-starred as Bailey Todd on the second season of Epix's Graves the following year, and subsequently appeared as a fun-loving reiki healer on the HBO comedy series Camping (2018), a remake of the British show of the same name.

[101] In Tate Taylor's 2019 psychological horror film Ma, Lewis played the mother of a teenage girl who grows close to a disturbed woman in their neighborhood.

[106] Lewis starred on the Showtime mystery thriller series Yellowjackets between November 2021 and May 2023, portraying Natalie Scatorccio, a plane crash survivor haunted by painful secrets.

[107][108] The show was received enthusiastically by critics,[109] with The Guardian's Leila Latif calling Lewis "sublime", noting that "[she] stunningly performs the nuances of tentative empathy and glimmers of optimism within a deep chasm of grief".

Richard Roeper called the latter "colorful and shiny but increasingly dark and twisted" in his review for the Chicago Sun-Times, adding that Lewis' portrayal of forthright costume designer Denise Coughlan was "outstanding".

[124] Lewis is known for acting in films such as National Lampoon's Christmas Vacation (1989), Cape Fear (1991), Husbands and Wives (1992), What's Eating Gilbert Grape (1993), Natural Born Killers (1994), From Dusk till Dawn (1996), The Other Sister (1999), Old School (2003), Conviction (2010), August: Osage County (2013), and Nerve (2016).

She was also nominated for a Primetime Emmy Award for Outstanding Supporting Actress in a Limited or Anthology Series or Movie for her role playing a flirty teenager in the HBO film Hysterical Blindness (2002) and as an outspoken costume designer in the Hulu miniseries Welcome to Chippendales (2022).