In 1951, O'Connor was diagnosed with systemic lupus erythematosus, like her father, and subsequently returned to her ancestral farm, Andalusia, in Milledgeville, Georgia. Although expected to live only five more years, she managed fourteen. At Andalusia, she raised and nurtured some 100 peafowl. Fascinated by birds of all kinds, she raised ducks, ostrich, emus, toucans, and any sort of exotic bird she could obtain, while incorporating images of peacocks into her books. She describes her peacocks in an essay entitled "The King of the Birds." Despite her sheltered life, her writing reveals an uncanny grasp of the nuances of human behavior. She was a devout Catholic living in the "Bible Belt," the Protestant South. She collected books on Catholic theology and at times gave lectures on faith and literature, traveling quite far despite her frail health. She also maintained a wide correspondence, including such famous writers as Robert Lowell and Elizabeth Bishop. She never married, relying for companionship on her correspondence and close relationship with her mother.
O'Connor completed more than two dozen short stories and two novels while battling lupus. She died on August 3, 1964, at the age of 39, of complications from new attack of Lupus following surgery for Fibroma, at Baldwin County Hospital and was buried in Milledgeville, Georgia, at Memory Hill Cemetery.