Neal had lung cancer and died at her home in Edgartown, Mass., on Martha's Vineyard, said longtime friend Bud Albers of Knoxville.
Neal was already an award-winning Broadway actress when she won her Oscar for her role as a housekeeper to the Texas father (Melvyn Douglas) battling his selfish, amoral son (Paul Newman).
Less than two years after winning the Academy Award, she suffered a series of strokes in 1965 at age 39. Her struggle to regain walking and talking is regarded as epic in the annals of stroke rehabilitation. She returned to the screen to earn another Oscar nomination and three Emmy nominations.
The Patricia Neal Rehabilitation Center that concentrates on helping people recover from strokes and spinal cord and brain injuries is named for her in Knoxville, where she grew up.
"She never forgot us after she went to Hollywood," said the 85-year-old Albers, who graduated with Neal from Knoxville High School in 1943.
Whenever she was in town, a bunch of her friends would always get together and have dinner, Albers said. Her family let him know of her death.
"She was so courageous," he said of her battling back from her illnesses and losing her 7-year-old daughter to measles in 1962. "She always fought back. She was very much an inspiration."
In her 1988 autobiography, "As I Am," she wrote, "Frequently my life has been likened to a Greek tragedy, and the actress in me cannot deny that comparison."
She made a grand return to the screen in 1968, winning an Oscar nomination for her performance in "The Subject Was Roses."
In 1971, she played Olivia Walton in "The Homecoming: A Christmas Story," a made-for-TV film that served as the pilot for the CBS series "The Waltons." It brought her the first of her three Emmy nominations.
"You can't give up," she said in a 1999 Associated Press interview. "You sure want to, sometimes."
In 1953, she married Roald Dahl, the British writer famed for "Charlie and the Chocolate Factory," "James and the Giant Peach" and other tales for children. They had five children. They divorced in 1983 and he died in 1990.
Even before her own illness, her life often was touched by misfortune. Besides her daughter's death, an infant son nearly died in 1960 when his carriage was struck by a taxi.
Neal also suffered a nervous breakdown, and had an ill-fated affair with Gary Cooper, who starred with her in "The Fountainhead."
"I lived this secret life for several years. I was so ashamed," she told The New York Times in 1964.
She and Dahl divorced after she learned he was having an affair with her best friend.
The strokes at first paralyzed her and impaired her speech. After recovering, she limped and had bad vision in one eye.
A 1991 biopic about her travails starred Glenda Jackson as Neal. Neal was born in a mining camp in Packard, Ky., the daughter of a transportation manager for the South Coal & Coke Co. After leaving Knoxville, she attended Northwestern University and then struck out for Broadway.
After doing well there, she made her screen debut in 1949's "John Loves Mary," that also starred Jack Carson and Ronald Reagan.
Among Neal's children is Tessa Dahl, who followed in her father's footsteps as a writer. Tessa Dahl's daughter is the model and writer Sophie Dahl.
Friends said her sorrows gave her an inner toughness that brought new power to her screen portrayals.
"I don't lie down. ... I'm fightin' all the way," she said in 1999.