Plimpton's acting career spanned from the mid-1960s to the late-1980s. She created the role of "Crissy" in the original 1967 Off-Broadway production of Hair, and continued the role as a member of the original Broadway cast when the production moved to Broadway in 1968. In both productions, she sang the song "Frank Mills". Shelley Plimpton took a leave of absence from Hair to appear in Arlo Guthrie's film Alice's Restaurant, playing a 14-year-old who offers herself to Arlo, saying that she has already "made it" with several other Musicians and "you'll probably be an album some day." He gently rejects her advances, giving her his bandana as a souvenir and saying simply, "I just don't want to catch your cold." Plimpton also appeared in the 1969 Robert Downey, Sr., film Putney Swope as one half of an interracial college couple ("It started last weekend at the Yale-Howard game") in a satire of a pimple cream TV spot. She sings a duet, in which she concludes: "My man uses Face Off / He's really out of sight, and so are his pimples." In 1971, Plimpton appeared in Jim McBride's post-apocalyptic drama film, Glen and Randa, in which she portrays Randa, a young woman part of a group of scavengers who survived a nuclear apocalypse many years prior and sets off with her lover Glen (Steve Curry) to discover a ravaged world and to search for a city which Glen has seen in comic books. She worked with McBride once again when she was cast in the 1974 comedy film Hot Times. Her final film role was in the 1975 film Forplay.

In 1970, Plimpton gave birth to Martha Plimpton (whose father is Keith Carradine) New York City, where she raised her in Manhattan's Upper West Side. From 1970 to 1971, Plimpton was married to Steve Curry. From 1990 to 1997, she was married to theatre Director Daniel Sullivan (who worked as an assistant Director on Hair, and later directed the Seattle Repertory Theater).

Plimpton made a brief return to acting in 1986 when she made a guest appearance on the short-lived television sitcom Throb, which starred Diana Canova, Paul Walker and Jane Leeves, after which she retired from acting.

In 2002, it was reported that Plimpton was living in Seattle, Washington, working a day job at a gift center. In September 2017, Vanity Fair reported that she resided in her native Oregon.