Black then went to New York. She studied drama with Lee Strasberg and appeared in a number of Off-Broadway productions. She was an understudy in the Broadway play Take Her, She's Mine (1961), and debuted in The Playroom (1965), which she received good reviews for.
Her film debut was in The Prime Time (1960). Her first big role was as Amy Partlett in You're a Big Boy Now (1966), which was directed by Francis Ford Coppola and starred Elizabeth Hartman and Geraldine Page. Black became a star with her role as Karen in Easy Rider (1969). She has over 100 film performances to her credit, including her role as Fran in Hitchcock's Family Plot (1976).
She won a Golden Globe for Best Supporting Actress for Five Easy Pieces, and she won a Golden Globe for Best Supporting Actress - Motion Picture for her role as Myrtle Wilson in The Great Gatsby (1974). She was nominated for Best Motion Picture Actress - Drama for her role as Faye Greener in The Day of the Locust (1975).
Black has had two husbands, screenwriter Kit Carson (divorced), and film editor Stephen Eckelberry (married 1987-present). She and Carson have one son, Hunter Carson (born December 25, 1975); and she and Eckelberry adopted one daughter at three months of age, Celine Eckelberry (born December 1987).
She also appeared on the TV series The Hundred Years (1967) as Marcia Garroway. And she has made a number of guest starring appearances on popular shows, including The Big Valley, Mannix, Adam-12, Saturday Night Live, Murder, She Wrote and Law & Order: Criminal Intent.
In March 2005, Karen Black received the Best Actress Award at the Fantasporto International Film Festival in Porto, Portugal, for her work in the film Firecracker (2004), in which she plays two roles, Sandra and Eleanor. She and actor John Hurt were both presented with Career Achievement Awards as well.