Mare Winningham was first seen in the American drama series ‘James at 15’ in 1977. She went on to appear in television series such as ‘Police Woman’ (1978), ‘The Young Pioneers’ (1978), ‘Starsky and Hutch’ (1979), ‘Family’ (1979), before making her big-screen debut in the 1980 feature film ‘One-Trick Pony’ directed by Robert M. Young. The following year, she was seen playing the role of ‘Carol Severance’ in the Canadian drama/science fiction film, ‘Threshold.’ In 1985, she starred as ‘Wendy Beamish’ in the American coming-of-age film ‘St. Elmo's Fire’ directed by Joel Schumacher. The film was marred by negative reviews from critics but managed to come out as a commercial success. She next appeared in films like ‘Nobody's Fool’ (1986), ‘Shy People’ (1987), ‘Miracle Mile’ (1988), ‘Turner & Hooch’ (1989), ‘Hard Promises’ (1991), ‘Sexual Healing’ (1993), and ‘Teresa's Tattoo’ (1994). She portrayed ‘Mattie Blaylock’ in the 1994 American biographical Western film ‘Wyatt Earp’ directed by Lawrence Kasdan. The film received mixed to negative reviews from critics.
In 1995, she was seen playing the role of ‘Georgia Flood’ in the Ulu Grosbard-directed American independent film ‘Georgia.’ Despite opening to positive reviews, the film failed to perform at the box office. Nevertheless, Winningham received the ‘Academy Award,’ ‘Independent Spirit Award,’ and ‘Screen Actors Guild Award’ nominations for her performance in the film. She continued to star in films like ‘Bad Day on the Block’ (1997), ‘The Adventures of Ociee Nash’ (2003), ‘Dandelion’ (2004), ‘War Eagle, Arkansas’ (2007), ‘Swing Vote’ (2008), ‘Brothers’ (2009), ‘Mirror Mirror’ (2012), ‘Philomena’ (2013), and ‘Geostorm’ (2017). In 2018, she starred as ‘Janice’ in the American drama fiction film ‘O.G.’ directed by Madeleine Sackler. The film received positive reviews from critics and scored an approval rating of 89% on Rotten Tomatoes. That same year, she also appeared in the American historical drama film ‘The Seagull’ which opened to a mixed reception. In 2019, she was seen playing the role of ‘Darlene Kiger’ in the American legal thriller film ‘Dark Waters.’ The film was widely praised by critics. Winningham was last seen in the 2021 Canadian drama film ‘All My Puny Sorrows’ directed by Michael McGowan.