Schedule:
| Game | Date | Away Team (Rank) | Away Score | Home Team (Rank) | Home Score | Game Status | Result | Margin |
|---|---|---|---|---|---|---|---|---|
| 1 | 2021-09-04 | Texas Tech | 38 | Houston | 21 | Final | L | -17 |
| 2 | 2021-09-11 | Houston | 44 | Rice | 7 | Final | W | 37 |
| 3 | 2021-09-18 | Grambling | 0 | Houston | 45 | Final | W | 45 |
| 4 | 2021-09-25 | Navy | 20 | Houston | 28 | Final | W | 8 |
| 5 | 2021-10-01 | Houston | 45 | Tulsa | 10 | Final | W | 35 |
| 6 | 2021-10-07 | Houston | 40 | Tulane | 22 | Final | W | 18 |
| 7 | 2021-10-23 | East Carolina | 24 | Houston | 31 | Final(OT) | W | 7 |
| 8 | 2021-10-30 | SMU | 37 | Houston | 44 | Final | W | 7 |
| 9 | 2021-11-06 | Houston | 60 | South Florida | 42 | Final | W | 18 |
| 10 | 2021-11-13 | Houston | 37 | Temple | 8 | Final | W | 29 |
| 11 | 2021-11-19 | Memphis | 13 | Houston | 31 | Final | W | 18 |
| 12 | 2021-11-27 | Houston (20) | 45 | Connecticut (196) | 17 | Final | W | 28 |
| 13 | 2021-12-04 | Houston (22) | 20 | Cincinnati (2) | 35 | Final | L | -15 |
| 14 | 2021-12-28 | Houston (17) | 17 | Auburn (43) | 13 | Final | W | 4 |