Caldwell was born in a house in the woods outside Moreland, Georgia, the son of a minister in the Associate Reformed Presbyterian Church. His early childhood was spent moving from state to state across the South, as his father found a position in one church after another.
Later, he attended, but did not graduate from, Erskine College. He was athletic, played football, stood six feet tall, and has been described by one of his publishers to have an unusually kind face and otherwise angelic appearance. His political sympathies lay with blue collar workers, and as he went from job to job in his younger days, drew on his experiences with common workers to write books that extolled the simple life of those less fortunate than he was. Later in life, he gave seminars on low income tenant-sharecroppers in the American South.
His first and second published works were Bastard (1929) and Poor Fool (1930) but the works for which he is most famous are his novels Tobacco Road (1932) and God's Little Acre (1933).
When his first book came out, it was banned and copies were seized by authorities. Later, on the publication of God's Little Acre, authorities went even further and, at the instigation of the New York Literary Society (apparently incensed at Caldwell's choice of titles), arrested Caldwell and seized his copies when he went to New York for a book-signing event. A full trial exonerated Caldwell completely, and he counter-sued for false arrest and malicious prosecution.
Through the 1930s, Caldwell and his wife ran a bookstore in Maine. Caldwell was married to photographer Margaret Bourke-White from 1939 to 1942, and they collaborated on You Have Seen Their Faces (1937).
At the height of World War II, Caldwell obtained papers from the USSR that allowed him to travel to Ukraine and work as a foreign correspondent documenting the war effort there. Disillusionment with the stifling intrigues of the Stalinist regime led him to pen a four page short story, "Message for Genevieve," published on returning to the United States in 1944. In this story, a woman journalist is executed by a firing squad after being tried in a secret court on charges of espionage.
After he came back from World War II, Caldwell took up residence in San Francisco. His ex-wife kept the bookstore in Maine as a property settlement.
During the last twenty years of his life, he got into the habit of traveling around the world for six months out of each year, and he took with him numerous notebooks to jot down his ideas on. Many of these notebooks were not published, but became part of his legacy upon his death, and can be examined in a museum dedicated to him. The house he was born in was moved from its initial site and preserved, and was made into a museum closer to town.Caldwell, a heavy smoker, died from complications of emphysema and lung cancer on April 11, 1987, aged 83. He is interred in Scenic Hills Memorial Park, Ashland, Oregon.