Born in Joliet, Illinois on March 17, 1918, McCambridge began her career in radio in Chicago. She made her Broadway debut in 1945 in the short-lived A Place of Our Own, and her last appearance on Broadway was as a replacement in Neil Simon's Lost in Yonkers. In 1972, she received a Tony Award nomination for her featured role in The Love Suicide at Schofield Barracks. Her other Broadway credits were Woman Bites Dog, The Young and Fair, and Who's Afraid of Virginia Woolf?
In 1950, McCambridge won an Academy Award for her movie debut in All the King's Men. She appeared in such other notable films as Giant, Johnny Guitar, A Farewell to Arms, Suddenly, Last Summer, and Cimarron, and she famously provided the voice of the devil in The Exorcist (1973).
McCambridge's autobiography, The Quality of Mercy, was published in 1981. The actress's personal life was troubled by alcoholism, two failed marriages, and her son's killing of himself, his wife, and their two children in 1987.