Born in Middletown, Connecticut, James Guy received his formal training at the Hartford Art School, where he was taught by Albertus E. Jones, a painter of post-impressionist landscapes. During his formative years, he painted expressionistic landscapes and still lifes influenced by modernist painters such as Charles Burchfield and George Grosz. Guy’s talent quickly caught the attention of A. Everett “Chick” Austin, Jr., the progressive-minded director of the Wadsworth Atheneum. Under Austin’s guidance, the Atheneum became one of the first American institutions to exhibit and acquire examples of surrealist painting for its permanent collection, thus providing Guy with the opportunity to view the work of Salvador Dali, Giorgio de Chirico, and others firsthand. Austin’s pioneering 1931 exhibition, New Super-Realism (the first exhibition of European Surrealism in the United States), played an especially significant role in shaping Guy's art.
After 1932, Guy began spending most of his time in New York, where he took classes at the Art Students League and viewed the work of European surrealists at the Museum of Modern Art and the Julien Levy Gallery. He was particularly impressed by Dali’s precise painting style and bright palette, as well as by his practice of incorporating real and imagined objects into his eerie, dream-like environments. At the same time, Guy’s affinity for social surrealism went hand-in-hand with his involvement with several left-wing political organizations, such as the Unemployed Artists Group, the Artists’ Union, and the John Reed Club, whose members believed that art could serve as a vehicle for social and governmental change. For Guy, this idea was reinforced when he went to Mexico, where he spent six months studying under the mural painter José Clemente Orozco, who specialized in political subjects.
During the 1930s, Guy painted a mural (since lost) for the 13th Street Communist Works School, as well as mural decorations for public schools in Hartford and Meriden, Connecticut, working under the auspices of the Works Progress Administration.
Guy exhibited his social surrealist work in group shows at the Whitney Museum of American Art, the Art Institute of Chicago, and the American Artists’ Congress, among other venues. They were likewise featured in solo exhibitions held at the Ferargil Galleries in New York in 1941 and 1944. From 1942 until 1945, Guy worked in an aircraft factory, where he was drawn to the planar forms of gliders. He subsequently abandoned Surrealism and social commentary in favor of brightly colored geometric abstractions influenced by artists such as Ferdinand Leger. In the 1960s, Guy further adapted to the changing tastes of his time by producing assemblages and constructions in which he explored the creative potential of materials such as plexiglass.
Guy spent most of his time in New York until moving back to Connecticut in about 1940. During the next twenty years, he operated a summer art school in East Hampton, Connecticut, along with his first wife, Clara Skinner, a printmaker and illustrator. Guy also held teaching positions at Bennington College (1945–47), MacMurray College (1946–54), and Wesleyan University (1961–75). In 1954, he relocated to Moodus, Connecticut, where he remained (with the exception of seasonal trips to Florida) until his death in 1983.