Winger was born as Mary Debra Winger in Cleveland Heights, Ohio into an Orthodox Jewish family, to Robert Winger, a meat packer, and Ruth Felder, an office manager. She has stated publicly and with amusement that the Internet has a growing "snowball" of claims that she had been part of a kibbutz in Israel, whereas she was merely on a typical Israeli youth program that visited the kibbutz. After returning to the States, she was involved in a car accident and suffered a cerebral hemorrhage as a result. She was left partially paralyzed and blind for ten months, although she was initially told that she would never see again. With time on her hands to think about her life, she decided that, if she recovered, she would move to California and become an actress. She later recovered.

Winger's first acting role was as "Debbie" in the 1976 sexploitation film Slumber Party '57. Her next role was as Diana Prince's younger sister Drusilla (Wonder Girl) on the TV show, Wonder Woman.

Her first starring role was in Thank God It's Friday, followed by her role of a cowgirl in Urban Cowboy in 1980 with John Travolta, for which she received a BAFTA nomination. In 1982, she co-starred with Nick Nolte in Cannery Row and with Richard Gere in An Officer and a Gentleman, for which she was nominated for the Academy Award for Best Actress. She was nominated for the Academy Award for Best Actress twice more: for Terms of Endearment in 1983 and for Shadowlands in 1993, for which she also received her second BAFTA nomination. Her performance in A Dangerous Woman earned a Golden Globe nomination for Best Actress.

Over the years, Winger acquired a reputation for being outspoken and sometimes difficult to work with. She has expressed her dislike of An Officer and a Gentleman, for which she refused to do any publicity, and several other of her films, and has been dismissive of some of her co-stars and directors. Commenting on her past attitudes, Winger said in 2009, "Most bad behaviour comes from insecurity. Even though I loved what I was doing, I didn't always know I could pull it off. (...) I took [my insecurities out] on everybody. But, in my defence, I never fought about the size of my trailer or things like that; it was always about the work".

Winger was cast in the lead role in A League of their Own but dropped out and was replaced by Geena Davis.

In 1995, Winger decided to take a hiatus from acting. In 2002 she said, "I wanted out for years. I got sick of hearing myself say I wanted to quit. It's like opening an interview with "I hate interviews!" Well, get out! I stopped reading scripts and stopped caring. People said, "We miss you so much." But in the last six years, tell me a film that I should have been in. The few I can think of, the actress was so perfect". After making Forget Paris in 1995, she was absent from the screen for six years, before returning in 2001 with Big Bad Love.

From November 1999 to January 2000, Winger had the female lead in the American Repertory Theater's production of Anton Chekhov's play Ivanov.

In 2001, a critically acclaimed documentary film titled Searching for Debra Winger was made by Rosanna Arquette and released in 2002 after Winger returned to film acting. Other films included Legal Eagles, Made in Heaven, Everybody Wins, The Sheltering Sky, Leap of Faith, Black Widow, Betrayed, Wilder Napalm, A Dangerous Woman and Sometimes in April. She earned an Emmy Award nomination for her title role in the television film Dawn Anna in 2005, directed by her second husband, Arliss Howard.

In 2008 she got positive reviews as Anne Hathaway's estranged mother in Rachel Getting Married.

She made a guest appearance as a high school principal in an episode of Law & Order which aired in March 2010.