In 1970 Kuper and his childhood friend Seth Tobocman published their first fanzine, Phanzine, and in 1971 they published G.A.S Lite, the official magazine of the Cleveland Graphic Arts Society. In 1972 Kuper traded R. Crumb some old jazz records for the right to publish some artwork from one of Crumb's sketchbooks in a comic titled Melotoons that lasted for two issues.
Kuper has travelled extensively through Latin America, Europe, Africa, the Middle East and Southeast Asia, much of which he documented in his 1992 book, ComicsTrips: A Journal of Travels Through Africa and Southeast Asia.
Spy vs. Spy had passed through various hands after its creator Antonio Prohías retired, but Kuper's version has appeared without interruption since 1997.
Kuper's Eye of the Beholder was the first comic strip to ever regularly appear in the New York Times, and his quasi-autobiography Stop Forgetting To Remember: The Autobiography of Walter Kurtz covers the birth of his daughter, 9/11, and other vicissitudes in his life from 1995-2005.
Though permanently based in New York City, Kuper and his wife and daughter resided in the Mexican state of Oaxaca 2006-2008, where he documented an ongoing teachers' strike and other aspects of Mexico in his sketchbook journal Diario de Oaxaca.
Kuper's work in comics and illustration frequently combines techniques from both disciplines, and often takes the form of wordless comic strips. Kuper remarked on this, "I initially put comics on one side and my illustration in another compartment, but over the years I found that it was difficult to compartmentalize like that. The two have merged together so that they're really inseparable."
Kuper won a journalism award from The Society of Newspaper Designers in 2001. His wordless picture story Sticks and Stones was awarded the 2004 gold medal, and his comic "This Is Not A Comic" won a silver medal in 2009 both from the Society of Illustrators. He won another gold medal in the sequential arts category from the Society of Illustrators in 2010.