Hunter made her screen debut in the 1981 horror movie The Burning. After moving to Los Angeles, California in 1982, Hunter appeared in TV-movies before being cast in a supporting role in 1984's Swing Shift. That year, she had her first collaboration with the writing-directing-producing team of brothers Ethan Coen and Joel Coen, in Blood Simple, making an uncredited appearance as a voice on an answering-machine recording. More film and television work followed until 1987, when thanks to a starring role in the Coens' Raising Arizona and her Academy Award-nominated turn in Broadcast News, Hunter became a critically acclaimed star. She went on to the screen adaptation of Henley's Miss Firecracker; Steven Spielberg's Always, a romantic drama with Richard Dreyfuss; and the made-for-TV docudrama about the titular Supreme Court abortion case, Roe vs. Wade (1989).

Following her second collaboration with Dreyfuss, in Once Around (1991), Hunter garnered critical appreciation for her work in three 1993 films, two of which resulted in her being nominated for two Academy Awards the same year: Hunter's performance in The Firm won her a nomination as Best Supporting Actress, while her portrayal of a mute Scottish woman entangled in a treacherous affair with Harvey Keitel in Jane Campion's The Piano won her the Best Actress award. Hunter went on to appear in films such as the comedy-drama Home for the Holidays (1995) and the thriller Copycat (1995). Her work in David Cronenberg's Crash (1996) did win her strong notices, but it was swallowed by the controversies surrounding the film, and her appearance as a sardonic angel in A Life Less Ordinary (1997) suffered a similar fate. The following year, she played a recently divorced New Yorker in Richard LaGravenese's Living Out Loud; starring alongside Danny DeVito, Queen Latifah, and Martin Donovan, Hunter won positive reviews for her performance. Hunter rounded out the 1990s with a minor role in the independent drama Jesus' Son and as a housekeeper torn between a grieving widower and Kiefer Sutherland's drama Woman Wanted (1999).

Following a supporting role in the Coens' O Brother, Where Art Thou? (2000), Hunter took top billing in the same year's television movie Harlan County War, an account of labor struggles among Kentucky coal-mine workers. Hunter would continue her small screen streak with a role in When Billie Beat Bobby (2001), playing tennis pro Billie Jean King in the fact-based story of King's famed exhibition match with Bobby Riggs; and as narrator of Eco Challenge New Zealand before returning to film work with a minor role in the 2002 drama Moonlight Mile. The following year found Hunter drawing favorable reviews for her role in the otherwise critically maligned redemption drama Levity. Also in 2003, Hunter had a supporting role in the acclaimed film Thirteen for which she received a Best Supporting Actress Oscar nomination.

In 2004, Hunter starred alongside Brittany Murphy in the romantic satire Little Black Book, and the same year lent her voice to the animated film The Incredibles as the voice of Helen Parr, a.k.a. the superheroine Elastigirl. In 2005, Hunter starred along side Robin Williams in the black comedy-drama The Big White. Hunter became an executive producer, and helped develop a starring vehicle for herself with the TNT cable-network drama Saving Grace, which premiered in July 2007. For her acting, she received a Golden Globe Award nomination, a Screen Actors Guild Award nomination, and an Emmy Award nomination. On May 30, 2008 Hunter received a star on the Hollywood Walk of Fame.

• "Saving Grace" .... Grace Hanadarko / ... (23 episodes, 2007-2009)
       - I Believe in Angels (2009) TV episode .... Grace Hanadarko
       - So What's the Purpose of a Platypus? (2009) TV episode .... Grace Hanadarko
       - The Heart of a Cop (2009) TV episode .... Grace Hanadarko
       - You Are My Partner (2008) TV episode .... Det. Grace Hanadarko
       - Are You an Indian Princess? (2008) TV episode .... Det. Grace Hanadarko
        (18 more)
• The Big White (2005) .... Margaret
  ... aka Grand blanc, Le (Canada: French title)
  ... aka The big White - Immer Ärger mit Raymond (Germany)
• Nine Lives (2005) .... Sonia
• The Incredibles (2004) (voice) .... Helen Parr / Elastigirl
• Little Black Book (2004) .... Barb
• Thirteen (2003) .... Melanie 'Mel' Freeland
• Levity (2003) .... Adele Easley
• Moonlight Mile (2002) .... Mona Camp
• When Billie Beat Bobby (2001) (TV) .... Billie Jean King
  ... aka Billie contre Bobby: La bataille des sexes (Canada: French title)
• "Abraham and Mary Lincoln: A House Divided" (2001) TV mini-series (voice) .... Mary Lincoln
  ... aka American Experience: Abraham and Mary Lincoln - A House Divided (USA)
• Harlan County War (2000) (TV) .... Ruby Kincaid
• O Brother, Where Art Thou? (2000) .... Penny
  ... aka O' Brother (France)
• Timecode (2000) .... Renee Fishbine, Executive
• Woman Wanted (2000) .... Emma Riley
• Things You Can Tell Just by Looking at Her (2000) .... Rebecca Waynon (segment "Fantasies About Rebecca")
  
• Jesus' Son (1999) .... Mira