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) in three episodes of ABC's TV series, Wonder Woman. The producers had wanted her to appear more often, but she refused, fearing that the role would hurt her fledgling career. This was followed by a guest role in Season 4 of the TV drama Police Woman in 1978.

Winger's three-year relationship with actor Andrew Rubin ended in 1980. From 1983 to 1985 Winger dated Bob Kerrey, at the time the Governor of Nebraska, whom she met while filming Terms of Endearment in Lincoln, Nebraska. Winger has also dated her Cannery Row and Everybody Wins co-star Nick Nolte.

Winger has had feuds with some of her co-stars, notably Richard Gere of An Officer and a Gentleman (1982) and Shirley MacLaine of Terms of Endearment (1983).

From 1986 to 1990 she was married to actor Timothy Hutton with whom she had a son, Noah Hutton, a documentary filmmaker born in 1987. The marriage ended in divorce.

In 1995 Winger performed in The Wizard of Oz in Concert: Dreams Come True a television musical performance of the popular 1939 MGM film at Lincoln Center to benefit the Children's Defense Fund. Her roles in that television special were the "Cyclone" narrator and the Wicked Witch of the West. It was originally broadcast on both TBS and TNT.

In 1996 she married actor/director Arliss Howard, whom she met on the set of the film Wilder Napalm. Their son, Gideon Babe Ruth Howard (known as Babe), was born in 1997. She is stepmother to Sam Howard, Arliss's son from his prior marriage.

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

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. She subsequently starred in the films Radio, Eulogy, Sometimes in April and received positive reviews for portraying Anne Hathaway's estranged mother in Rachel Getting Married.

She earned an Emmy Award nomination for her title role in the television film Dawn Anna in 2005, directed by Arliss Howard. In 2010 she returned to television, making a guest appearance as a high school principal in an episode of Law & Order. She also joined the cast of HBO's In Treatment as one of the three patients featured in the third season.

During her hiatus from the film industry, Winger spent a semester as a teaching fellow at Harvard University. In 2008 Winger wrote a book based on her personal recollections titled Undiscovered. She has shown her support for reconciliation between Arabs and Jews in Israel by visiting the bilingual Hand in Hand schools (Galilee Jewish-Arab School, Gesher al HaWadi School) where, in 2008, she stated she would "dedicate the next bit of my life to these schools".

As 2009 President of the Zurich Film Festival jury, Winger joined other members of the Hollywood film community to speak out against the arrest and prosecution of Director Roman Polanski who was convicted of raping a 13-year-old girl in the 1970s, criticizing Switzerland's government for "philistine collusion" in arresting him so many years later, as he was en route to attend the Zurich festival.

In 2010 Debra Winger was co-executive Producer of the Academy Award-nominated documentary, Gasland. She was also the executive Producer of the 2012 documentary Bel Borba Aqui about the life and works of Brazilian graphic Artist Bel Borba.

Her other acting project is a starring role in the upcoming film In the Woods, the first installment of Jennifer Elster's multimedia, experimental film series The Being Experience, planned for multi-platform release in 2013 and 2014, also including: Terrence Howard, Dave Matthews, Rufus Wainwright, Karen Black, Will Shortz, Liya Kebede, Questlove, Famke Janssen, Moby, Gale Harold, Paz de la Huerta, Jorgen Leth, Rosie Perez, Aubrey de Grey, and Alan Cumming. She also stars opposite Sam Elliott and Ashton Kutcher in the 2016 Netflix multi-cam comedy The Ranch. She also had a cameo as Supreme Court Justice Elena Kagan in the TV Miniseries When We Rise.

In 2017, she starred in her first romantic lead after many years in The Lovers. She has continued to acquire roles in other feature films, such as Tiger City, scheduled for release in 2018.