Hugely prolific, the Illinois-born actress appeared in more than 100 movies over a career spanning 40 years.
She shot to fame in 1969, starring as a prostitute in Easy Rider opposite Peter Fonda and Dennis Hopper.
She died at a clinic in Los Angeles, three years after she was diagnosed with cancer.
Her fourth husband, Stephen Eckelberry, posted the news on his Facebook page.
“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,” he wrote.
“Thank you all for all your prayers and love, they meant so much to her as they did to me.”