Winningham was raised in Northridge, California with three brothers and one sister. Her father was the Chairman of the Department of Physical Education at California State University, Northridge (CSUN) and her mother was an English teacher and college counselor at a local high school. She credits her first interest in acting to seeing an interview with Kym Karath (who played "Gretl" in The Sound of Music) on Art Linkletter's television show House Party when she was five or six years old.

Winningham attended Andasol Avenue Elementary School in Northridge, California - her favorite subjects included drama. She also signed up for guitar lessons at a local park, and by the 6th grade was, in her view, "pretty good". It was at this time that she adopted the nickname "Mare". She attended Patrick Henry Junior High School, taking the extended drama option, and on summer vacations she studied drama at CSUN's Teenage Drama Workshop.

Though she was supposed to attend Granada Hills High School, instead Winnigham's mother assisted her in entering Chatsworth High School, as it was renowned for its drama department. In Grade 12 Winningham starred in the school's senior production of The Sound of Music, playing the part of Maria, opposite Kevin Spacey as Captain Von Trapp.

Though born an Irish Catholic, in 2000 Winningham felt her spiritual life was lacking, and, based on a recommendation from a friend, in November 2001 she signed up for a class given by Rabbi Neal Wienberg at the University of Judaism in Los Angeles, California. On March 3, 2003 she converted to Judaism, and became a member of two Conservative synagogues, Temple Beth Am in Los Angeles, and Temple Knesset Israel in Hollywood, California.

Winningham was married to the actor A Martinez; they divorced in 1981. In 1982 she married William Maple; they are now divorced. Winningham has four children, Riley Maple (1981-2005), Patrick and Jack Maple (born 1985) and Calla Louise Maple (born 1987).

Winningham began her entertaining career as a struggling singer-songwriter. In 1976 she got her break singing the John Lennon-Paul McCartney composition "Here, There, and Everywhere" on "The Gong Show." Though Winningham received no record contracts as result of the appearance, she was signed to an acting contract by Hollywood agent Meyer Mishkin, and received her Screen Actor's Guild card for doing three lines in an episode of James at 15. That year she was offered a role on Young Pioneers and Young Pioneers Christmas, pilots for the short-lived 1978 pioneer drama The Young Pioneers. Though the series ended with just three episodes being broadcast, a number of television projects followed, including parts on Police Woman in 1978 and Starsky and Hutch in 1979.

In 1980 Winningham won a Best Supporting Actress Emmy Award for her role in the critically acclaimed Amber Waves, a TV movie about a rough farmer (Dennis Weaver) who finds he is dying of cancer. In that year she also broke into film in One Trick Pony, starring Paul Simon. In 1983 Winningham was nominated for a Canadian Genie Award for her work in the futuristic 1981 drama Threshold, and appeared in the epic miniseries The Thorn Birds. In 1984 she starred as Helen Keller in Helen Keller: The Miracle Continues.

Winningham achieved greater fame in 1985's St. Elmo's Fire as one of the original "brat pack" alumni. Despite the film's success, she refused to cash in on her teen idol status, and returned to television in the Hallmark Hall of Fame movie, Love Is Never Silent, for which she received an Emmy nomination. Winningham finished the 80s with two Hollywood films, the nuclear disaster drama Miracle Mile (1988), for which she received an Independent Spirit Award nomination in 1989, and the Tom Hanks vehicle Turner & Hooch in 1989. In 1988 Winningham also starred in the Los Angeles stage production of Hurlyburly with Sean Penn and Danny Aiello.

The early 90s brought a number of forgettable television projects as Winningham took a break to be with her husband, William Maple, and five children. She returned to film for 1994's all-star Wyatt Earp and the family drama The War, both starring Kevin Costner.

1995 brought Georgia, a thoughtful character study of two sisters (Winningham and Jennifer Jason Leigh), which earned Winningham Golden Globe Screen Actors Guild Award and Academy Award nominations. Two years later, she starred opposite Gary Sinise in George Wallace, for which she garnered another Golden Globe Award nomination, and won an Emmy Award.

Since then she made acclaimed appearances on the series "ER" and "Law and Order: SVU," as well as appearances in the 2001 television project Sally Hemmings, opposite Sam Neill and the short-lived David E. Kelley series "The Brotherhood of Poland, New Hampshire." Winningham's most recent project is the independent film Dandelion, which was a staple of film festivals worldwide between 2003 and 2004 and is set for a limited American release in October of 2005.

Winningham has also recorded two albums, What Might Be on the Bay Cities label, and Lonesomers, on the Razor and Tie label.