| 2021-09-12 | 1 | @ |  NYG | 27-13 | W | -3 | 41.5 | MetLife Stadium |
| 2021-09-19 | 2 | @ |  JAX | 23-13 | W | -6 | 45 | TIAA Bank Stadium |
| 2021-09-26 | 3 | vs |  NYJ | 26-0 | W | 10.5 | 42 | Empower Field at Mile High |
| 2021-10-03 | 4 | vs |  BAL | 7-23 | L | 1 | 44 | Empower Field at Mile High |
| 2021-10-10 | 5 | @ |  PIT | 19-27 | L | -2 | 40 | Heinz Field |
| 2021-10-17 | 6 | vs |  LV | 24-34 | L | 5 | 45.5 | Empower Field at Mile High |
| 2021-10-21 | 7 | @ |  CLE | 14-17 | L | 2 | 40.5 | FirstEnergy Stadium |
| 2021-10-31 | 8 | vs |  WAS | 17-10 | W | 4 | 45 | Empower Field at Mile High |
| 2021-11-07 | 9 | @ |  DAL | 30-16 | W | 10.5 | 50 | AT&T Stadium |
| 2021-11-14 | 10 | vs |  PHI | 13-30 | L | 1 | 44.5 | Empower Field at Mile High |
| 2021-11-28 | 12 | vs |  LAC | 28-13 | W | -2.5 | 47.5 | Empower Field at Mile High |
| 2021-12-05 | 13 | @ |  KC | 9-22 | L | 8.5 | 46.5 | GEHA Field at Arrowhead Stadium |
| 2021-12-12 | 14 | vs |  DET | 38-10 | W | 13 | 42 | Empower Field at Mile High |
| 2021-12-19 | 15 | vs |  CIN | 10-15 | L | 3 | 45 | Empower Field at Mile High |
| 2021-12-26 | 16 | @ | LV | 13-17 | L | -1 | 42 | Allegiant Stadium |
| 2022-01-02 | 17 | @ | LAC | 13-34 | L | 8 | 45.5 | SoFi Stadium |
| 2022-01-08 | 18 | vs | KC | 24-28 | L | -11.5 | 44.5 | Empower Field at Mile High |
