By the summer of 1952, O'Connor was diagnosed with systemic lupus erythematosus (lupus), as her father had been before her. Subsequently, she returned to the family farm, Andalusia, in Milledgeville, Georgia. 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.
O'Connor completed more than two dozen short stories and two novels while suffering from lupus. She died on August 3, 1964, at the age of 39 in Baldwin County Hospital. Her death was caused by complications from a new attack of lupus following surgery for a fibroma. She was buried in Milledgeville, Georgia, at Memory Hill Cemetery.