Her breakthrough came in 1998 when she starred in Robert Rodriguez's sci-fi horror film The Faculty, receiving positive reviews for her portrayal of "Stokes" Mitchell, a goth high school student.

[7] DuVall had roles in several films released in 1999, including biographical drama Girl, Interrupted, where she appeared as compulsive liar Georgina Tuskin; teen romantic comedy She's All That, which opened atop the U.S. box office;[8] and the independent features Wildflowers and But I'm a Cheerleader.

[13] DuVall appeared as a regular cast member on the HBO drama series Carnivàle between 2003 and 2005, with the Los Angeles Times pointing out that her portrayal of tarot card reader Sophie was "especially good".

[15] Subsequent credits included guest appearances on CSI: Crime Scene Investigation (2005), Lie to Me (2009), Numb3rs, Bones, and Law & Order (all 2010), as well as key parts in films such as David Fincher's critically acclaimed Zodiac (2007),[16] and the recurring role of Audrey Hanson on the NBC science fiction series Heroes (2006–2007).

The latter received mixed reviews, but critics praised the performances of Ricci and DuVall; writing for The Hollywood Reporter, Keith Uhlich said the actresses "have a delectable rapport not too far removed from Bette Davis and Joan Crawford at their hag-horror peak in What Ever Happened to Baby Jane?

[19][20] Acquired by Paramount Pictures after its premiere at the 2016 Sundance Film Festival,[21] the comedy-drama was positively reviewed; Andy Webster of The New York Times noted that "DuVall juggles the emotional dynamics with fluid editing and light comic touches".

From 2016 to 2019, DuVall played Marjorie Palmiotti on the HBO political satire Veep, for which she was twice nominated—alongside her co-stars—for the Screen Actors Guild Award for Outstanding Performance by an Ensemble in a Comedy Series, winning in 2018.

[23] She also starred in the independent comedy-drama All About Nina (2018), and played Sylvia in several episodes of the dystopian Hulu drama series The Handmaid's Tale between 2018 and 2022, with Judy Berman of Time calling it "the best work of [DuVall's career]".