Born in Woodmere, Long Island, to an upper middle-class family, Keller graduated from Cornell University in 1936 and enrolled at the Art Students League from 1937 to 1941, where he studied with Harry Sternberg and the printmaker Will Barnet. Among his first lithographs was a series entitled Sandhogs, produced between 1937 and 1941, which showed builders working on the Sixth Avenue Subway in Manhattan.

In 1940 Keller, who always had independent means, joined the Communist Party USA and remained a committed lifelong member. His social realist art arose from his political activism. Together with Gwathmey, Becker and Lozowick, from 1942 to 1949 he was active in running the left-wing Artists' League of America (ALA) whose aim was 'to bring more art to more people through the widest possible extension of both private and governmental sponsorship of art' (Membership flier; cited by Andrew Hemingway, Artists on the Left: American Artists and the Communist Movement 1926-1956, New Haven and London: Yale University Press, 2002, p. 192). Keller took part in many ALA exhibitions, most notably in a 1943 group show entitled 'This is Our War' at the Wildenstein Gallery, New York. He was instrumental in organizing exhibitions such as the 1943 group exhibition 'Art, a Weapon of Total War', held at the New School for Social Research, New York. From 1942 to 1945 he ran the ALA's Victory Workshop.

In 1945 Keller joined the Graphic Workshop where he produced his own work and organized group projects, such as the print portfolios Yes, the People! and Negro USA, which reflected the co-operative nature of the workshop. Keller also produced posters and leaflets for various labor campaigns and worked with the Progressive Citizens of America organization. In 1945 he became art editor of the Marxist publication New Masses until it closed in 1948. He placed a new emphasis upon the visual impact of the periodical, commissioning work from Gwathmey and Harari, as well as contributing his own political cartoons.

In the post-war period, under the climate of McCarthyism, Keller came under political pressure. In 1961 he left America to live and work in Italy, where he was based principally in Rome and where he held several solo exhibitions over the next ten years before returning to the United States. In 1976 a full retrospective of his work was held at the Herbert F. Johnson Museum of Art at Cornell University.