Guyon attended and played college football at the Carlisle Indian Industrial School from 1912 to 1913 under head coachPop Warner. Sportswriters often tried to call him "Injun Joe" after the character in The Adventures of Tom Sawyer, but it never much caught on outside the press. The 1912 team posted a 12–1–1 record, scored 454 points, and was Jim Thorpe's greatest season. Guyon played on the team as left tackle. In the game against Army featuring the likes of future US President Dwight D. Eisenhower, Leland Devore was ejected for manhandling Guyon. The 1913 team went 10–1–1, scoring 296 points. Guyon shifted to Thorpe's place at halfback and was honored by Walter Camp as a second-team All-American.
Keewatin
From 1914 to 1915, Guyon attended the Keewatin Academy in Prairie du Chien, Wisconsin, to regain college eligibility.
Guyon then attended and played football at Georgia Tech from 1917 to 1918 under head coach John Heisman. Guyon was used mainly as a halfback. His brother Charles "Wahoo" Guyon was the assistant coach. For his time spent playing at Georgia Tech, Guyon was a unanimous selection for an Associated Press Southeast Area All-Time football team 1869-1919 era. Fullback Judy Harlan said about Guyon, "Once in a while the Indian would come out in Joe, such as the nights Heisman gave us a white football and had us working out under the lights. That's when Guyon would give out the blood curdling war whoops."
1917
The 1917 team went 9–0, scored 491 points, was crowned national champion, and was for many years considered "the greatest the South ever produced." Guyon played right halfback, where he was the team's power back and best passer. He was a unanimous All-Southern selection, and considered by some the South's best back. His first run from scrimmage for Tech was a 75-yard touchdown against Wake Forest. In a 63–0 rout of Washington & Lee, Guyon knocked a Washington & Lee player out of the game by "wearing an old horse collar shaped into a shoulder pad but reinforced with a little steel" according to Judy Harlan. Against Vanderbilt University he had arguably his greatest game, running 12 times for 344 yards in an 83–0 blowout. According to sportswriter Morgan Blake, "Guyon has been great in all games this year. But Saturday he was the superman". Against Tulane, each of the four members of the backfield eclipsed 100 yards rushing. "Strupper, Guyon, Hill, and Harlan form a backfield with no superiors and few equals in football history" wrote the Times-Picayune. He passed for two touchdowns and ran for one, passing 91 yards and running 112: "Guyon's passing was so accurate it suggest possibilities yet undeveloped in the Tech offense". In the large, 68–7 win over Auburn, Guyon once dove at its star Moon Ducote and missed, but Guyon gave chase from behind and tackled him at the 26-yard line.
1918
The 1918 team went 6–1, scoring 462. Guyon was used mainly as a fullback, though sometimes as a tackle. He was honored as a tackle on Frank G. Menke's first All-America team.
Guyon had previously hit over.340 three consecutive years for the Louisville Colonels in the American Association, which at AA, was at the highest classification of the era. His playing career as an outfielder extended from 1920 through 1936 with a break during his college coaching career.
