Hurst was born in Hamilton, Ohio, the only surviving child of a well-to-do Jewish family. She spent the first twenty years of her life in St. Louis, Missouri, where she attended Washington University in St. Louis and graduated in 1909. In 1915 she married Jacques S. Danielson of New York, a pianist, but the marriage was not announced until five years later.

In 1921, Hurst was among the first to join the Lucy Stone League, an organization that fought for women to preserve their maiden names. She was active in the Urban League, and was appointed to the National Advisory Committee to the Works Progress Administration in 1940. She was also a delegate to the World Health Organization in 1952.

When Hurst and Arctic explorer Vilhjalmur Stefansson were having a long affair, they often met in New York City's Greenwich Village at Romany Marie's café when Stefansson was in town; he was a regular there for many years and a good friend of the proprietor.

Hurst hosted a talk show out of New York called Showcase beginning in 1958. Showcase was notable for presenting several of the earliest well-rounded discussions of homosexuality and was one of the few on which homosexual men spoke for themselves rather than being debated by a panel of "experts". Hurst was praised by early homophile group the Mattachine Society which invited Hurst to deliver the keynote address at the Society's 1958 convention.

F. Scott Fitzgerald presciently described her as one of several authors "not producing among 'em one story or novel that will last 10 years."

Hurst died in 1968, at the age of 78, in New York City. The first full biography of Hurst, by Brooke Kroeger, was published in 1999.

Story collections

• Just Around the Corner (1914)
• Every Soul Hath Its Song (1916)
• Gaslight Sonatas (1918)
• Humoresque (1919)
• The Vertical City (1922)
• Song of Life (Knopf, 1927)
• Procession (1929)
• We are Ten (1937)

Novels

• Stardust: The Story of an American Girl (1921)
• Lummox (1923)
• Mannequin (Knopf, 1926)
• Appassionata (Knopf 1926)
• A President is Born (1928)
• Five and Ten (1929)
• Back Street (1931)
• Imitation of Life (1933)
• Anitra's Dance (1934)
• Great Laughter (1936)
• Lonely Parade (1942)
• Hallelujah (1944)
• The Hands of Veronica (1947)
• Anywoman (1950)
• The Man with One Head (1951)
• Family! (1960)
• God Must Be Sad (1961)
• Fool, Be Still (1964)

Autobiography

• Anatomy of Me: A Wonderer in Search of Herself (1958)

Miscellaneous

• No Food with My Meals (1935)
• White Christmas (1942)