Centre opened the season with three straight wins by a combined score of 241–0, beating , 66–0; the
Howard Bulldogs, 120–0; and , 55–0. A prequel to the
1921 Centre vs. Harvard football game followed;
Harvard had not lost a game since 1918 and defeated visiting Centre 31–14, finishing with a record of 8–0–1. With the Harvard game tied 7–7, it was 4th down and 6 at the 30-yard line. Instead of
punting, McMillin "defied every "don't" in the football book" and tossed a
touchdown pass. A loss at
Georgia Tech followed, 24–0; Georgia Tech finished its season 8–1, having outscored its opponents 312–16. One writer recalled he heard a story that Tech tackle
Bill Fincher sought to knock
Bo McMillin out of the game, taking with him
brass-knuckles or "something equally diabolical." Centre then defeated , 34–0, in
Indianapolis;
Kentucky, 49–0, at
Lexington;
VPI, 28–0, in
Louisville; and the , 103–0. ==Postseason==