An eight-time Emmy Award nominee, she won Outstanding Supporting Actress in a Miniseries or Movie for Amber Waves in 1980 and George Wallace in 1998.

Winningham's other film and TV roles include The Thorn Birds (1983), St. Elmo's Fire (1985), Miracle Mile (1988), Turner & Hooch (1989), The War (1994), Dandelion (2004), Swing Vote (2008), Brothers (2009), Mildred Pierce (2011), Hatfields & McCoys (2012), and appeared in American Horror Story for four seasons: Coven (2013), Freak Show (2014), Hotel (2015–16), and Cult (2017).

Winningham made her New York stage debut in the 2007 Off-Broadway musical 10 Million Miles, for which she received a Drama Desk Award nomination.

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, where her favorite activities included drama and playing the guitar and drums.

In grade 12, Winningham starred in a production of The Sound of Music, playing the part of Maria, opposite classmate Kevin Spacey as Captain Von Trapp.

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.

Later that same year, she played the role of teenage outcast Jenny Flowers in the made-for-TV film The Death of Ocean View Park.

She then won an Emmy Award for Best Supporting Actress in a Miniseries or a Movie for her role in the critically acclaimed Amber Waves, a television film about a rough farmer (Dennis Weaver) who finds he is dying of cancer.

In 1983, Winningham was nominated for a Canadian Genie Award for her work in the futuristic 1981 drama Threshold, and appeared in the 1983 epic miniseries The Thorn Birds, in which she played Justine O'Neill.

[3] Winningham achieved greater fame co-starring in St. Elmo's Fire (1985), alongside the other original "brat pack" alumni.

[3] Despite the film's success, she chose not to cash in on her teen idol status, and soon returned to television in the Hallmark Hall of Fame movie, Love Is Never Silent, for which she received an Emmy nomination.

Winningham finished the 1980s 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.

[12] In 2012, she appeared Off-Broadway as Beth, the mother in an intellectual, though dysfunctional, British family, in the award-winning comic-drama Tribes by Nina Raine.

The country/bluegrass/Jewish/folk songs on Refuge Rock Sublime deal mostly with her recent conversion to Judaism, and include the tracks, "What Would David Do," "A Convert Jig" and the Israeli national anthem "Hatikva".