Nagurski played tackle and end on defense and fullback on offense at the University of Minnesota (1927–29) and was named All-American (All-America team) at tackle in 1929. Nagurski became a legendary figure during his collegiate years. An oft-repeated tale that circulated through the popular press described Nagurski's discovery by his college coach: lost on a recruiting trip, the coach asked a strapping farmer for directions to the nearest town, and the farmer, young Nagurski, pointed the way—with his plow.

In 1930 Nagurski joined the National Football League (NFL) Chicago Bears, where, playing fullback, he used his skill as a rusher, passer, and blocker to help the Bears win NFL championships in 1932 and 1933. He retired in 1937 because of a salary dispute and the unwillingness of the Bears management to allow him to wrestle professionally, which paid better. He continued to wrestle until 1942, but in 1943 he returned to the Bears, who were in need of players because of the manpower demands of World War II. Playing mostly tackle, Nagurski helped the Bears win the NFL championship that season. He was enshrined in the Pro Football Hall of Fame in 1963.