Born in Berkeley, California Karen studied ballet, acted in school plays, sang in the Baptist choir. She graduated from The University of California with bachelor degrees in 1965 in English and in Dramatic Art. She received a Fulbright Fellowship to the London Academy of Music and Dramatic Art in London, and apprenticed at the Actor's Workshop of San Francisco in 1961–62.

Karen played the role of the ma, Caroline Ingalls, in the Little House on the Prairie TV series from 1974 to 1983. Subsequently, she acted in the features Harry's War, a 1981 American film and Wyatt Earp, a 1994 film starring Kevin Costner. During this period, she lobbied for federal funding for shelters for battered women and appeared in many events to support the Equal Rights Amendment.

She later moved to Santa Fe, New Mexico and became co-founder and artistic director of Santa Fe's Resource Theater Company. Later she moved to Louisville, Kentucky, where she performed with the company of actors at Actors Theatre of Louisville.

Karen's memoir, Bright Lights, Prairie Dust: Reflections on Life, Loss and Love from Little House's Ma was released on November 16th.