She began acting at age 14 with a Golden Globe-nominated breakout role in Lipstick (1976), and she received Academy and BAFTA Award nominations for her performance in Woody Allen's Manhattan (1979).

She had leading roles in Personal Best (1982), Star 80 (1983), and the TV series Civil Wars for which she received a Golden Globe nomination.

Reports circulated for years that Hemingway had her breasts enlarged to play the role of Stratten, but during a 2007 appearance on the late-night talk and variety show, Fashionably Late with Stacy London, she said she had had the surgery before Star 80.

She was cast as the female lead in Darren Star's CBS drama Central Park West for the 1995–96 season; however, the show fared poorly with both critics and viewers, and after 13 episodes Hemingway was told that the show wanted her to accept a deep pay cut and demotion to recurring character status.

Hemingway is heterosexual, but has said she formed a "big connection with the LGBT community" after Personal Best and enjoys taking roles in "cutting-edge" productions.

[11] Hemingway worked on the documentary film Running from Crazy, directed by Barbara Kopple and produced by the Oprah Winfrey Network chronicling the Hemingway family's history of suicide, substance abuse and mental illness,[12] shown at the Sundance Film Festival in 2013.

In October that year, Hemingway received a humanitarian award from the San Diego Film Festival for her role in the documentary.

[16] In early 2011, Hemingway began a relationship with former stuntman Bobby Williams with whom she has co-authored a self-help book.

[17][19] In the 2013 television documentary Running from Crazy,[20] Hemingway talked of her bouts of mental illness and her still lingering issues with her siblings.