Kupperberg began writing and drawing for Marvel Comics in 1974, mostly doing fill-ins and one-shots. Eventually, he had runs on team books like The Invaders, The Avengers, and The Defenders; and drew a number of issues of What If.
Also occasionally working as a writer, Kupperberg created the 1983 one-shot comic Obnoxio the Clown vs. The X-Men as a one-man band, handling everything from writing and illustrating to lettering, unusual for the comic industry at that time. In 1987, Kupperberg worked on both Spectacular Spider-Man and Amazing Spider-Man. From 1988—1991, Kupperberg drew many issues of Marvel Tales.
He also worked for Marvel Custom Comics, for clients such as Campbell's Soup, the U.S. Department of Energy, the Sylvan Learning Center, and The Dallas Times Herald.
From the mid-1980s into the early 1990s, Kupperberg illustrated such DC Comics titles as Justice League of America,Warlord, The Fury of Firestorm, DC Comics Presents, COPS, and Dragonlance. He had a long run on Blue Devil.
In 1978 Kupperberg and writer Marv Wolfman took over the Howard the Duck weekly newspaper strip with; Kupperberg also worked on the short-lived Incredible Hulk strip. His newspaper work also includes Little Orphan Annie.
Kupperberg has done illustrations for Archie Comics, National Lampoon, Cracked magazine, Spy, and McClannahan Books.
Outside of comics
He worked on script development and character design for Sullivan Bluth Studios' 1994 animated feature Thumbelina. From 1994, he worked with Nickelodeon/Viacom on the Tom Terrific animated project.
He has also done design work and scripting for numerous advertising and production agencies. His autobiographical strips have appeared in Comic Art and in the Streetwise book.