She was born Lula Carson Smith in Columbus, Georgia in 1917. Her mother was the granddaughter of a plantation owner and Confederate war hero. Her father, similar to Wilbur Kelly in The Heart Is a Lonely Hunter, was a watchmaker and jeweler of French Huguenot extraction. From the age of ten she took piano lessons, and at the age of 15 she received a typewriter from her father.

In September 1934 at age 17 she left home on a steamship from Savannah, Georgia, planning to study piano at the Juilliard School of Music in New York City, but never attended the school, having lost the money set aside for her tuition. McCullers worked in menial jobs and studied creative writing under Texas writer Dorothy Scarborough at night classes at Columbia University and with Sylvia Chatfield Bates at Washington Square College of New York University. She decided to become a writer and published in 1936 an autobiographical piece, Wunderkind, a piece her course teacher Miss Bates much admired, in Story magazine. It depicted a musical prodigy's failure and adolescent insecurity and also appears in The Ballad of the Sad Cafe collection.

From 1935 to 1937 she divided her time, as her studies and health dictated, between Columbus and New York and in September 1937 she married an ex-soldier and aspiring writer, Reeves McCullers. They began their married life in Charlotte, North Carolina where Reeves had found some work. There, and in Fayetteville, North Carolina, she wrote her first novel, The Heart Is a Lonely Hunter, in the Southern Gothic tradition. The title, suggested by McCullers's editor, was taken from Fiona MacLeod's poem "The Lonely Hunter." However, many (including Carson McCullers) claim she wrote in the style of Southern Realism, a genre inspired by Russian Realism. The novel itself was interpreted as an anti-fascist book. Altogether she published eight books. The Heart Is a Lonely Hunter (1940), written at the age of twenty-three, Reflections in a Golden Eye (1941) and The Member of the Wedding (1946), are the best-known. The novella The Ballad of the Sad Cafe (1951) also depicts loneliness and the pain of unrequited love. She was an alumna of Yaddo in Saratoga, New York.

The Heart Is a Lonely Hunter was filmed in 1968 with Alan Arkin in the lead role. Reflections in a Golden Eye was directed by John Huston (1967), starring Marlon Brando and Elizabeth Taylor. Some of the film was shot in New York City and on Long Island, where Huston was permitted to use an abandoned Army installation. Many of the interiors and some of the exteriors were done in Italy. "I first met Carson McCullers during the war when I was visiting Paulette Goddard and Burgess Meredith in upstate New York," said Huston in An Open Book (1980). "Carson lived nearby, and one day when Buzz and I were out for a walk she hailed us from her doorway. She was then in her early twenties, and had already suffered the first of a series of strokes. I remember her as a fragile thing with great shining eyes, and a tremor in her hand as she placed it in mine. It wasn't palsy, rather a quiver of animal timidity. But there was nothing timid or frail about the manner in which Carson McCullers faced life. And as her afflictions multiplied, she only grew stronger."

McCullers and Reeves separated in 1940 and divorced in 1941. After she separated from Reeves, she moved to New York to live with George Davis, the editor of Harper's Bazaar. In Brooklyn, she became a member of the art commune February House. Among their friends were W. H. Auden, Benjamin Britten, Gypsy Rose Lee, and Paul and Jane Bowles. After World War II, Carson lived mostly in Paris. Her close friends during these years included Truman Capote and Tennessee Williams.

In 1945, Carson and Reeves McCullers remarried. Three years later, she attempted suicide while depressed. In 1953, Reeves tried to convince her to commit suicide with him, but she fled. After Carson left, Reeves killed himself in their Paris hotel with an overdose of sleeping pills. Her bittersweet play, The Square Root of Wonderful (1957), was an attempt to examine these traumatic experiences. The Member of the Wedding (1946) describes the feelings of a young girl at her brother's wedding. The Broadway production of the novel had a successful run in 1950—51 and was produced by the Young Vic in London in September 2007.

McCullers suffered throughout her life from several illnesses and from alcoholism ... she had contracted rheumatic fever at the age of fifteen and suffered from strokes since her youth. By the age of 31, her left side was entirely paralyzed. She died in Nyack, New York, on September 29, 1967, after a brain hemorrhage, and was buried in Oak Hill Cemetery. McCullers dictated her unfinished autobiography, Illumination and Night Glare (1999), during her final months. Her home from 1945 to 1967 was listed on the National Register of Historic Places in 2006.

"Mrs McCullers and perhaps Mr. Faulkner are the only writers since the death of D. H. Lawrence with an original poetic sensibility. I prefer Mrs McCullers to Mr. Faulkner because she writes more clearly; I prefer her to D. H. Lawrence because she has no message." — Graham Greene

"[Her work is] one of the few satisfying achievements of our second-rate culture." — Gore Vidal

"Moving, yes, but a minor author. And broken by illness at such a young age." — Arthur Miller

"Carson's major theme; the huge importance and nearly insoluble problems of human love." — Tennessee Williams.

Although McCullers's oeuvre is often described as "Southern Gothic," she produced her famous works after leaving the South. Her eccentric character suffer from loneliness that is interpreted with deep empathy. In a discussion with the Irish critic and writer Terence de Vere White she said: "Writing, for me, is a search for God." Other critics have variously detected tragicomic or political elements in her writing.

McCullers' narration of The Member of the Wedding was used by Jarvis Cocker on his debut album, Jarvis. It forms the introduction to the song "Big Julie" and consists of an edited (or slightly mangled) version of the opening lines of the book:

"It happened that green and crazy summer. It was a summer when for a long time she had not been a member. She belonged to no club and she was a member of nothing in the world. And she was afraid."

Sue Denim of the band Robots in Disguise references McCullers along with other writers in the song "For JT and Carson and Emily". in her solo project Sue and the Unicorn.

Nanci Griffith's album Clock Without Hands is in part inspired by McCullers' novel.

The Heart Is a Lonely Hunter is referred to in the movie A Love Song for Bobby Long; the main character's mother always carried the novel with her and read it over and over again.

Charles Bukowski wrote an eponymous poem about her.

Tennessee Williams dedicated his 1948 play Summer and Smoke and the poem Which is my little boy (Jean qui rit) to her.

In the movie Con Air, Ving Rhames's character Diamond Dog is said to have written a memoir entitled Reflections in a Diamond Eye.

Novels

• The Heart Is a Lonely Hunter (1940)
• Reflections in a Golden Eye (1941)
• The Member of the Wedding (1946)
• Clock Without Hands (1961)

Other works

• The Ballad of the Sad Cafe (1951), a short story collection comprising:
• a novella of the same title, later made into a Merchant Ivory Film,
• Wunderkind — (Story, 1936)
• The Jockey — (The New Yorker, 1941)
• Madame Zilensky and the King of Finland — (The New Yorker, 1941)
• The Sojourner — (Mademoiselle, 1950)
• A Domestic Dilemma — (New York Post magazine section, September 16, 1951)
• A Tree, a Rock, a Cloud — (Harper's Bazaar, 1942)
• The Square Root of Wonderful (1958), a play
• Sweet as a Pickle and Clean as a Pig (1964), a collection of poems
• The Mortgaged Heart (1972), a posthumous collection of writings, edited by her sister Rita
• Illumination and Night Glare (1999), her unfinished autobiography, published more than 30 years after her death

Collections

• Complete Novels, Carlos L. Dews, ed. (New York: The Library of America, 2001) ISBN 978-1-93108203-7.