Nathan Wallenstein Weinstein was born in New York in 1903 to Jewish parents who immigrated from Russia. At Brown University in Rhode Island, he befriended legendary humorist S.J. Perelman—who later married West's sister—and drew cartoons and wrote surreal short stories, later compiled into the novel The Dream Life of Balso Snell (1931), which West completed while living in Paris after graduation. In 1926 he changed his name to Nathanael West.

West returned to the United States, working as a journalist and managing two hotels, where he gave writer-friends free room and board (although, unbeknownst to them, he extracted payment by steaming open his residents' mail, providing him with plenty of material for Miss Lonelyhearts).

In 1929, West got a chance to see some letters written to "Susan Chester," the advice columnist for the Brooklyn Eagle. While his friend Perelman declined to use the letters as source material, West saw their raw potential and fashioned the story of Miss Lonelyhearts around them. Several chapters were published serially in magazines, and the entire novel was published as one volume in 1933.

While briefly working as a screenwriter in 1933, West grew interested in the workings of Hollywood. He published A Cool Million: The Dismantling of Lemuel Pitkin, a more direct critique of the American Dream, in 1934. In 1935, he moved to Hollywood for good, working as a screenwriter and collecting material for The Day of the Locusts, which was ultimately published in 1939. This novel's tales of smashed hopes and corrupt power only mirrored West's personal experience only somewhat: though unemployed at first, he later made a decent run as a screenwriter, contributing to at least twelve movies made between 1936 and 1940. Fittingly, considering West's Hollywood involvement, Miss Lonelyhearts has been filmed four times, sometimes under different titles, most notably with Montgomery Clift playing "Adam White" in 1959's much-altered Lonelyhearts. The Day of the Locust was turned into a movie in 1975.

After a lifetime of financial insecurity, West was finally poised to make a success of himself in Hollywood, but a car crash on December 22, 1940, killed both him and his new wife, Eileen McKenney. Coincidentally, F. Scott Fitzgerald, a friend of West's, died the same weekend—the world at once lost two writers who saw through the glamour of the American Dream. Indeed, is fitting that The Day of the Locust and Fitzgerald's unfinished work The Last Tycoon stand together as the definitive Hollywood novels.

West's works are best read as studies of the dark side of Depression-era America. While West's contemporary John Steinbeck may have held an equally dour view of the purported American Dream—the belief that anyone could rise in social and economic standing—Steinbeck's writing is peopled with compassionate characters, such as the Joad family in The Grapes of Wrath, who provide emotional hope in a time of economic scarcity. In West's work, however, such humanity is in as short supply as money, resulting in tragedies that are more closely aligned with those of F. Scott Fitzgerald. West's focus on the interior dream-life of the masses found a perfect outlet in his Hollywood novel The Day of the Locust, but it was the New York novel Miss Lonelyhearts that gave West his first critical success. Despite the critical praise, West's novels never caught on commercially in his lifetime.