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Close gained early recognition for her work on the stage, with her Broadway debut in the play Love for Love (1974), before going on to win three Tony Awards, two for Best Actress in a Play for her roles in the plays The Real Thing (1983) and Death and the Maiden (1992), and one for Best Actress in a Musical, the musical Sunset Boulevard (1995). She received her first Academy Award nomination for her film debut in The World According to Garp (1982), and her first Emmy nomination in 1984 for the television film Something About Amelia. Close's career further progressed throughout the 1980s and 1990s with several acclaimed film performances, including The Big Chill (1983), The Natural (1984), Fatal Attraction (1987), Dangerous Liaisons (1988), Reversal of Fortune (1990), The Paper (1994), Mars Attacks! (1996), and Air Force One (1997). During this period, she also portrayed Cruella de Vil in 101 Dalmatians (1996) and its 2000 sequel 102 Dalmatians, and voiced Kala in Tarzan (1999).

Close won the Primetime Emmy Award for Outstanding Lead Actress in a Limited Series or Movie for her portrayal of Colonel Margarethe Cammermeyer in Serving in Silence: The Margarethe Cammermeyer Story (1995), followed by two consecutive Primetime Emmy Awards for Outstanding Lead Actress in a Drama Series for playing Patty Hewes in Damages (2007–2012). In film, Close gained continued recognition in the 21st century for her roles in Albert Nobbs (2011), The Wife (2017), Hillbilly Elegy (2020), and Wake Up Dead Man (2025).

Close is the president of Trillium Productions and co-founder of the website FetchDog. She has made political donations supporting Democratic politicians. She is vocal on issues such as women's rights, same-sex marriage, and mental health. Married three times, she has one daughter, Annie Starke, from her relationship with producer John Starke.