His early work was heavily influenced by the abstract expressionist painters, especially Willem de Kooning. His art became more popular in the 1960s and had his first one-man exhibition in 1962 at the Tanager Gallery, New York. After that, his art made it to several other exhibitions such as the Young America exhibition in 1965, Whitney Museum, New York.
Beginning in the 1950s, he made collages from magazine clippings and found objects, often incorporating female nudes. Wesselmann was best known for his "Great American Nudes" series.
He died of complications following heart surgery, aged 73.