Sewell Sillman began his art studies after he served in the US Army during World War II. He enrolled at the Black Mountain College in North Carolina, where the faculty members included former Bauhaus professor Josef Albers and his wife Anni, Buckminster Fuller, Merce Cunningham, Willem de Kooning, Walter Gropius and Robert Creeley. His most influential teacher there was Josef Albers, and when Albers left Black Mountain for a professorship at Yale University, Sillman decided to follow him to continue his studies there. From Yale he received a BFA in 1951 and then a MFA in 1953.

He was offered, and accepted a position on the faculty of Yale. He remained there until 1966. He subsequently taught at Rhode Island School of Design, the University of Michigan, and finally retired in 1990 from the University of Pennsylvania.

He co-founded Ives-Sillman, Inc. with fellow Yale artist Norman Ives, publishing fine art portfolios and individual prints for artists including Joseph Albers, Romare Bearden, Jean Dubuffet, Jacob Lawrence, Piet Mondrian, Ad Reinhardt, as well as a book on the theories of Joseph Albers.

He was widely exhibited during his life. His work was handled by both the Stable Galleries and Sidney Janus Gallery in NYC, and he is represented in the collections of the Museum of Modern Art, the Whitney Museum, and the Phillips Collection.