Ransom, whose father was a minister, lived during his childhood in several towns in the Nashville, Tenn., area. He attended Vanderbilt University in Nashville for two years, then dropped out to teach because he felt his father should not continue to support him. He later returned to the university and graduated in 1909 at the head of his class. Subsequently he went to Oxford University as a Rhodes scholar. From 1914 to 1937 he taught English at Vanderbilt, where he was the leader of the Fugitives, a group of poets that published the influential literary magazine The Fugitive (1922–25) and shared a belief in the South and its regional traditions.

Ransom was also among those Fugitives who became known as the Agrarians. Their I'll Take My Stand (1930) criticized the idea that industrialization was the answer to the needs of the South.

Ransom taught from 1937 until his retirement in 1958 at Kenyon College in Gambier, Ohio, where he founded and edited (1939–59) the literary magazine The Kenyon Review. Ransom's literary studies include God Without Thunder (1930); The World's Body (1938), in which he takes the position that poetry and science furnish different but equally valid knowledge about the world; Poems and Essays (1955); and Beating the Bushes: Selected Essays, 1941–1970 (1972). Ransom's poetry, which one critic has applauded as exhibiting weighty facts “in small or delicate settings,” often deals with the subjects of self-alienation and death. His poetry is collected in Chills and Fever (1924) and Two Gentlemen in Bonds (1927). Thereafter he published only five new poems; his Selected Poems (1945; rev. ed., 1969), which won a National Book Award, contains revisions of his earlier work. T.D. Young edited his critical essays (1968). Selected Essays of John Crowe Ransom appeared in 1984.