John Little was born in Sanford, Alabama. He left home at the age of fourteen to become an artist, and moved to Buffalo, New York, in 1923. After spending a year working as a stevedore on the docks to save money, he enrolled at the Buffalo Fine Arts Academy and developed an interest in singing. In 1927 he moved to New York City where he continued his vocal work and studied operatic literature. He also became involved in textile design, opening his own store in 1920, called John Little Studios: Fabric and Wallpaper Design. He ran the store until 1950.
In 1933 John Little resumed his painting studies at the Art Students League in New York under the guidance of George Grosz (1893-1959). The following year he made his first visit to East Hampton, Long Island, which he would eventually call home. Later in the decade, he traveled to Paris where he became familiar with European modernism. On his return to America, he taught textile design at the Pratt Institute in Brooklyn. He hired Josephine Watkins to work for him; she later became his wife. Little’s textile store and teaching job gave him a financial security that was rare during the Depression, and he never found it necessary to find employment with the Works Progress Administration. At the end of the decade, John Little studied with Hans Hofmann (1880-1966) in New York and Provincetown. Little was greatly influenced by Hofmann, particularly by his views on color theory.
In 1942 John Little joined the Navy as an aerial photographer. In the late 1940s he purchased a rundown house on Three Mile Harbor Road in East Hampton, near where he had been frequently visiting Jackson Pollock and Lee Krasner. In 1948 he had his first one-man show in New York at the Betty Parsons Gallery, where he would continue to exhibit frequently in the years ahead. He closed his textile business in 1950 and become a permanent resident of East Hampton, although he still maintained a studio in the city. In 1957 Little made an important contribution to the East Hampton scene when he opened the first commercial art gallery—Signa Gallery—with his artist friends Alfonso Ossorio (1916-1990) and Elizabeth Parker (1893-1975).
John Little continued to exhibit widely and travel and paint until his death in 1984. Examples of his work can be found in many important private and public collections including the Ball State University Museum of Art, Muncie, Indiana; Bruce Museum, Greenwich, Connecticut; Dillard University, New Orleans; Fine Arts Museums of San Francisco, California; Guild Hall Museum, East Hampton; Metropolitan Museum of Art, New York; and the University Art Museum, Berkeley, California.