By the summer of 1952, O'Connor was diagnosed with systemic lupus erythematosus (lupus),[28] as her father had been before her.[7] She remained for the rest of her life on Andalusia.[15] O'Connor lived for twelve years after her diagnosis, seven years longer than expected.
Her daily routine was to attend Mass, write in the morning, then spend the rest of the day recuperating and reading. Despite the debilitating effects of the steroid drugs used to treat O'Connor's lupus, she nonetheless made over sixty appearances at lectures to read her works.[15]
In the PBS documentary Flannery, the writer Alice McDermott explains the impact lupus had on O'Connor's work, saying, "It was the illness, I think, which made her the writer she is."[29]
O'Connor completed more than two dozen short stories and two novels while living with lupus. She died on August 3, 1964, at the age of 39 in Baldwin County Hospital.[15] Her death was caused by complications from a new attack of lupus following surgery for a uterine fibroid.[15] She was buried in Milledgeville, Georgia,[30] at Memory Hill Cemetery.