DuVall made her debut in the 1996 film Little Witches. This was followed by roles in several independent films and guest appearances on episodes of ER and Buffy the Vampire Slayer, before her breakthrough in 1998 as a goth student in Robert Rodriguez's The Faculty. She then portrayed a pathological liar in Girl, Interrupted, opposite Winona Ryder; and a lesbian undergoing conversion therapy in But I'm a Cheerleader. Major roles in The Astronaut's Wife (1999), Ghosts of Mars (2001) and Thirteen Conversations About One Thing (2001) followed.
After appearing in films such as The Laramie Project (2002), Identity (2003) and 21 Grams (2003), DuVall starred on HBO's Emmy Award-winning Carnivàle, which ran from 2003–2005. During that time, she also starred in Helter Skelter (2004), which earned her a nomination for the Satellite Award for Best Actress – Miniseries or Television Film, and in the box office hit The Grudge (2004).
Subsequent projects include a supporting role in David Fincher's Zodiac (2007), and a recurring character on NBC's hit sci-fi series, Heroes. In 2008, she appeared alongside Anne Hathaway in Passengers. This was followed by guest roles on Numb3rs, Bones, and Law & Order.
In 2012, she co-starred in the Ben Affleck film Argo, based on the Iran hostage crisis. DuVall played Cora Lijek, a Japanese-American who was one of the six American diplomats rescued from Iran in 1980. She, along with the rest of the Argo cast, received the Screen Actors Guild Award for Outstanding Performance by a Cast in a Motion Picture. That same year, DuVall appeared in a recurring role on the second season of the FX anthology series American Horror Story, as Wendy Peyser, the girlfriend of Lana Winters (Sarah Paulson).
In 2014, DuVall starred as Emma Borden, sister of Lizzie Borden (played by Christina Ricci), in the Lifetime TV movie, Lizzie Borden Took an Ax. She then reprised the role for Lifetime's eight-part series, The Lizzie Borden Chronicles (2015).
In 2016, DuVall made her feature directorial debut with The Intervention, which she also wrote, starred in, and executive produced. The film had its world premiere at the 2016 Sundance Film Festival on January 26, 2016.
It was reported in October 2017 that DuVall will star on the second season of Hulu's The Handmaid's Tale as the wife of Ofglen, played by Alexis Bledel.
