Born in Columbus, Mississippi, Williams was raised by his mother and maternal grandparents at an Episcopal rectory in Clarksdale, Mississippi; his father, a traveling salesman, was frequently absent. After a near-fatal bout of diphtheria, Williams remained a sickly child in the constant care of his overprotective mother. He also developed a close attachment to his older sister, Rose, who suffered from schizophrenia and, later, mental deterioration after an unsuccessful lobotomy. In 1923 his family moved to St. Louis, where his father was transferred to assume a managerial position. To relieve his sense of isolation in his new environment, Williams began to write poetry and short fiction. At the age of sixteen, he won an essay contest sponsored by Smart Set magazine; the essay, entitled “Can a Good Wife Be a Good Sport?,” became his first published work. In 1929 he entered the University of Missouri, though he was forced by his father to return home after failing ROTC in his third year. He took a menial job in a shoe warehouse and wrote short fiction and essays until suffering a nervous breakdown in 1935. During his convalescence, he collaborated on the comedy Cairo, Shanghai, Bombay! (1935). After that experience, he decided to devote himself to writing. He began taking classes at Washington University in St. Louis, but subsequently transferred to the University of Iowa. In 1938 he received his bachelor's degree in English. The next year he published “The Field of Blue Children” in Story magazine, his first work to appear under the name Tennessee. That same year, he received a Rockefeller Foundation fellowship, which allowed him to write his play Battle of Angels (1940).

In the early 1940s Williams was offered a salaried position with Metro-Goldwyn-Mayer in Hollywood; he produced several unaccepted screenplays, and was released at the