In the early 1960s, Zabriskie was among a circle of Kerry Thornley's New Orleans friends. At one point, Thornley began work on a novel about her called Can Grace Come Out and Play? Thornley later claimed to have had an "eight-year-long, off-again-on-again, affair/friendship/rivalry/ego-game/karmic unraveling" with her, though Zabriskie described it as "four and a half minutes in bed".

After making her major film debut in 1979's Norma Rae, Zabriskie went on to appear in dozens of other works, including the 1981 Roger Corman horror film Galaxy of Terror, and the 1981 miniseries adaptation of John Steinbeck's East of Eden. She played the nanny in 1980's The Private Eyes, Debra Winger's mother in An Officer and a Gentleman, Heather Langenkamp's mother in Nickel Mountain, and Paul Le Mat's mother in 1984's The Burning Bed (starring Farrah Fawcett). She also appeared in 1989's Drugstore Cowboy and as the ill-fated orphanage owner Grace Poole in Child's Play 2. Other movies include the 1991 film adaptation Fried Green Tomatoes and Philip Ridley's 1995 film The Passion of Darkly Noon.

Zabriskie may best be remembered as Mrs. Ross, a recurring character on the sitcom Seinfeld. She played the mother of another doomed daughter, Susan Ross — George Costanza's fiancée — who died after licking cheap envelope adhesive when mailing out her wedding invitations. Zabriskie's character's husband on the series, who also appeared in a recurring role, was played by her former Twin Peaks co-star, Warren Frost.

Her sister Jane Caplinger worked as a typist in New Orleans District Attorney Jim Garrison’s office. Caplinger is reputed to have covertly produced all five copies of the first edition of the Principia Discordia in 1965.