In college, Grange was a three-time consensus All-American and led his team to a national championship in 1923. He was the only consensus All-American running back in 1924 who was not a member of the Four Horsemen of Notre Dame. The same year, Grange became the first recipient of the Chicago Tribune Silver Football award as the Big Ten Conference's most valuable player. In 2008, Grange was named the best college football player of all time by ESPN, and in 2011, he was named the Greatest Big Ten Icon by the Big Ten Network.

Shortly after his final college game in 1925, Grange joined the Bears and the NFL, embarking on a barnstorming tour to raise the league's attention across the country. When his rookie contract expired, he and agent C. C. Pyle formed the American Football League in 1926, with Grange playing for the Yankees. The league lasted just one year before shutting down and the Yankees were assimilated into the NFL. Grange suffered a serious knee injury in 1927 that prevented him from playing the following season, and he returned to the Bears in 1929. He remained with the team until he ended his playing career in 1934, from which he became a backfield coach for the Bears for three seasons.

He is a charter member of both the College and Pro Football Halls of Fame.

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