The Colonels' victory in its game versus Harvard is regarded as one of the greatest upsets in college football history.

End Red Roberts was a first-team Walter Camp All-America selection, a rarity for a player in the South, and quarterback Bo McMillin made Camp's second team and was recognized as a consensus All-American.

[5] The Colonels had closed the 1920 season by convincingly routing Texas Christian (TCU) in the Fort Worth Classic, 63–7.

"[7][5] Coach Charley Moran used a single wing system like his former mentor Pop Warner.

[9] In 1921, football used a one-platoon system, with players featuring on both offense, defense, and special teams.

Center Red Weaver, who had posted record numbers for placekicking extra points,[10] graduated and was replaced with Ed Kubale.

This game marked the only time during the regular season that Centre gave up any points to an opponent.

"[26] "McMillin, Covington and Armstrong carried the ball 46 yards to the one-foot line on three plays" before Tanner went over and kicked goal for the lead.

[26] "The Colonels then showed their greatest offense when in five plays they took the ball 72 yards for a touchdown.

[26] Sources:[27] In the fourth week of play, Centre easily defeated Transylvania by the score of 98–0.

[27] According to Spalding's Football Guide, McMillin ran back a kickoff 95 yards for a touchdown.

[30] Some reports recall the players wearing work clothes to cultivate the image of the underdog.

[34] Harvard coach Bob Fisher said after the game: "In Bo McMillin Centre has a man who is probably the hardest in the country to stop.

[36] Tulane coach Clark Shaughnessy later wrote the win "first awoke the nation to the possibilities of Southern football.

"[37] In 1950, the Associated Press named C6H0 the greatest sports upset of the first half of the 20th century.

[41] In the middle of the second quarter, up 7–0, McMillin skirted left end and cut back across the field for a 49-yard touchdown.

[44] Judge Robert Worth Bingham hosted a dinner dance in honor of the two football teams.

Sources:[49] In the San Diego East-West Christmas Classic, Centre defeated Arizona 38–0 as rain fell throughout the game.

[53] Red Roberts was a first-team Walter Camp All-America selection, just the fourth in Southern history.

Bo McMillin made Camp's second team and is recognized as a consensus All-American.

Fuzzy Woodruff explains that Centre "belonged to no governing association"[59] with several players thereby accused of professionalism, and Tech was picked as champion "through force of habit".

[60] The following chart provides a visual depiction of Centre's lineup during the 1921 season with games started at the position reflected in parentheses.

[61][62] The following is an incomplete list of statistics and scores, largely dependent on newspaper summaries.