Born in Germany and raised in Wisconsin, Zuppke walked to West Division High School, where he studied art and learned the newly popular game of football. At Milwaukee Normal School, Zuppke, known as "Contrary Rob," was the quarterback on a losing football team, a center fielder on the baseball team, and a yearbook illustrator. In 1900 he was a guard on a winning basketball team. He went to the University of Wisconsin, where he played basketball and was a football substitute.

However, Robert Zuppke truly made his reputation just to the south in Illinois. In 29 years as football coach at the University of Illinois, Zuppke compiled a 131-81-13 record. His Illini teams won four national championships and seven Big Ten titles. Before going to Illinois, Zuppke led Oak Park High School in the Chicago suburbs to national championships in 1911-12.

Zuppke was known as an innovator and is credited with starting, among other things, the flea flicker, screen pass, spiral snap from center, spring practice and the huddle. He coached at Illinois longer than any other coach in university history.