Her film debut and breakthrough role came as Jacy Farrow in Peter Bogdanovich's coming-of-age drama The Last Picture Show (1971) alongside Jeff Bridges.

She also had roles as Kelly in Elaine May's The Heartbreak Kid (1972), Betsy in Martin Scorsese's Taxi Driver (1976), and Nancy in Woody Allen's Alice (1990).

Shepherd played Madelyn Hayes on the detective comedy-drama Moonlighting (1985–1989) opposite Bruce Willis, for which she won two Golden Globes for Best Actress in a Comedy/Musical TV Series out of three such nominations.

[6] According to Shepherd's autobiography, a 1970 Glamour magazine cover caught the eye of film director Peter Bogdanovich.

His then-wife, Polly Platt, claimed that when she saw the cover in a check-out line in a Ralphs grocery store in southern California, he said "That's Jacy,"[a] referring to the role Bogdanovich was casting—and ultimately given to Shepherd—in The Last Picture Show (1971).

[8] In 1974, Shepherd again teamed up with Peter Bogdanovich for the title role in Daisy Miller, based on the Henry James novella.

That same year, she launched a singing career, releasing a studio album Cybill Does It...To Cole Porter for MCA Records.

She portrayed Betsy, a volunteer for a presidential candidate with whom Robert De Niro's character, Travis Bickle, becomes infatuated.

Already sitting in on an acting class taught by Stella Adler, Shepherd was offered work at a dinner theater in Norfolk, Virginia, and turned to friend Orson Welles for advice.

He encouraged her to get experience on stage in front of an audience, anywhere but Los Angeles or New York City,[11] away from the harsh big-city critics[12] so she moved back to her home town of Memphis to work in regional theatre.

[13] In 1982, Shepherd returned to New York and to the stage when she played alongside James MacArthur in a theatre tour of Lunch Hour by Jean Kerr.

[14] The following year, Shepherd went back to Los Angeles and was cast as Colleen Champion in the NBC television drama The Yellow Rose (1983), opposite Sam Elliott.

In 2000, Shepherd's bestselling autobiography, Cybill Disobedience: How I Survived Beauty Pageants, Elvis, Sex, Bruce Willis, Lies, Marriage, Motherhood, Hollywood, and the Irrepressible Urge to Say What I Think, written in collaboration with Aimee Lee Ball, was published.

[21] In 2019, she took on a role as an ex-cop senior struggling with illness who unexpectedly finds love on a road trip in the direct-to-cable Being Rose.

Shepherd went home to Memphis, where she met and began dating David M. Ford, a local auto parts dealer and nightclub entertainer.

[30] She was present at the opening of the National Civil Rights Museum in her hometown of Memphis, to which she lent financial support.

[21] Nominations: In her autobiography,[23] Shepherd addressed rumors that she was jealous of her co-stars Bruce Willis and Christine Baranski for winning Emmy awards while she has not: "The grain of truth in this controversy was that of course I was envious.