The 74-year-old Easy Rider star passed away on Thursday at a nursing facility in Los Angeles, according to her husband Stephen Eckelberry, who broke the sad news on his Facebook page.
In a post he wrote: "It is with great sadness that I have to report that my wife and best friend, Karen Black has just passed away, only a few minutes ago. Thank you all for all your prayers and love, they meant so much to her as they did to me."
Black was diagnosed with ampullary cancer in November 2010, a rare form of the disease which affects the bile duct, and she had one third of her pancreas removed.
She went public with her health battle in 2012 and in March launched an appeal to help fund her treatment on crowdsourcing website Kickstarter.com, which managed to smash its $17,000 (£10,000) target.
Black appeared in over 100 movies but is perhaps best know for her role as Rayette Dipesto in 1970 movie Five Easy Pieces, for which she earned an Best Supporting Actress Academy Award nomination. She went on to win a Golden Globe and a New York Film Critics award for her portrayal of the waitress.
Throughout a career which spanned five decades, Black also starred in movies including The Great Gatsby, for which she also won a Golden Globe award, The Day of the Locust and Nashville.
She was married four times and had a son with writer L.M. (Kit) Carson.
She wed Eckelberry in 1987 and the pair adopted a daughter, named Celine.