The artist spent his childhood in and around Indianapolis. After military service, he attended the School of the Art Institute of Chicago on the GI Bill, graduating in 1953 with a fellowship to study art in Edinburgh. Upon his return to the United States in 1954, he settled in New York City. In 1958 he changed his last name to Indiana, assuming what he called his “nom de brush” and acknowledging his roots in the American Midwest.

Indiana began a series of paintings in 1961 with a bold sense of graphic design and an affinity for symmetry and the dynamics of American advertising, Sometimes critical of consumer tendencies or political excesses in American culture, Indiana's images combined stenciled text and numbers and hard-edged bright colour fields into compelling signs. His ever-popular Love design—first realized as a painting in 1966 and later created in many other media, including sculpture—became a Pop icon of the 1960s. On Valentine's Day, Feb. 14, 1973, the U.S. Postal Service issued Indiana's design as a commemorative stamp. Since 1978 Indiana has lived and worked in Vinalhaven, Maine.