God's Little Acre was published by Viking Press in 1933, one year after the publication of Tobacco Road. In it, Caldwell shifts his sights to the industrialized South. Influenced in part by the textile mill strikes in Gastonia, North Carolina, he considered this work to be a "proletarian" novel dealing with the plight of workers deprived of union protection. It was intended to support these mill hands, or "lintheads," as they were sometimes called. Will Thompson, who leads the strike, represents both the inherent power and the frustration of the working class. When Thompson is killed by guards as he attempts to reopen the mill shut down by its ruthless owners, his death becomes a rallying cry; and his corpse is borne through the streets, but the mills remain closed.
The book also examines the misuse of the land and other natural resources. Ty Ty Walden, who (unlike Jeeter Lester) still owns his farm, spends his time digging for gold instead of farming the rich soil. His delusion and the tragedy it brings to his family again illustrate the waste Caldwell saw in southern attitudes toward the land.
Like Tobacco Road, God's Little Acre contains scenes of explicit sexuality. In April 1933 the New York Society for the Suppression of Vice took Caldwell and Viking Press to court for dissemination of pornography. More than sixty authors, editors, and literary critics rallied in support of the book, and Judge Benjamin Greenspan of the New York Magistrates Court ruled in its favor. The court case is still considered a major decision in the establishment of artists' First Amendment rights in freedom of expression. The book became a worldwide best-seller and remains today one of the most popular novels ever published.