She was 69.
Duke passed away at 1:20 AM Tuesday morning. She died from sepsis due to a ruptured intestine.
Duke's son, Sean Astin, said the family is "relieved" because Duke was in a lot of pain and the process took a long time to play out.
Duke's family issued a statement, saying, "This morning, our beloved wife, mother, matriarch and the exquisite artist, humanitarian, and champion for mental health, Anna Patty Duke Pearce, closed her eyes, quieted her pain and ascended to a beautiful place."
"We celebrate the infinite love and compassion she shared through her work and throughout her life."
Duke was a child star -- winning the Oscar for Best Supporting Actress at 16 years old in 1963.
She was married 4 times ... including to actor John Astin -- the father of "Lord of the Rings" star Sean Astin.
Duke is survived by her husband, Michael Pearce, and her 3 kids.