| 1 | South Carolina over Florida 40–17 · at home · 2021-11-06 | 2021 | +20.5 | +43.5 | 10% | — |
| 2 | Rutgers over Indiana 38–3 · on the road · 2021-11-13 | 2021 | +6.5 | +41.5 | 34% | — |
| 3 | East Tennessee State over Vanderbilt 23–3 · on the road · 2021-09-05 | 2021 | +21 | +41.0 | 9% | — |
| 4 | Tennessee over Missouri 62–24 · on the road · 2021-10-02 | 2021 | +2.5 | +40.5 | 44% | — |
| 5 | Utah State over #19San Diego State 46–13 · on the road · 2021-12-04 | 2021 | +6.5 | +39.5 | 34% | 11 |
| 6 | Houston over Tulsa 45–10 · on the road · 2021-10-01 | 2021 | +3.5 | +38.5 | 41% | — |
| 7 | Georgia Tech over #21North Carolina 45–22 · neutral site · 2021-09-25 | 2021 | +14.5 | +37.5 | 18% | 9 |
| 8 | Ball State over Western Michigan 45–20 · on the road · 2021-10-09 | 2021 | +12.5 | +37.5 | 22% | — |
| 9 | Hawai'i over Wyoming 38–14 · on the road · 2021-11-27 | 2021 | +13 | +37.0 | 21% | — |
| 10 | Texas Tech over Mississippi State 34–7 · neutral site · 2021-12-28 | 2021 | +10 | +37.0 | 27% | — |
| 11 | UL Monroe over Troy 29–16 · at home · 2021-09-26 | 2021 | +23.5 | +36.5 | 7% | — |
| 12 | Army over Georgia State 43–10 · on the road · 2021-09-04 | 2021 | +2.5 | +35.5 | 44% | — |
| 13 | UL Monroe over Liberty 31–28 · at home · 2021-10-16 | 2021 | +32.5 | +35.5 | 2% | — |
| 14 | Utah State over San José State 48–17 · on the road · 2021-11-14 | 2021 | +4.5 | +35.5 | 39% | — |
| 15 | Bowling Green over Minnesota 14–10 · on the road · 2021-09-25 | 2021 | +30.5 | +34.5 | 3% | — |
| 16 | #12Notre Dame over #18Wisconsin 41–13 · neutral site · 2021-09-25 | 2021 | +6 | +34.0 | 35% | — |
| 17 | Kentucky over Louisville 52–21 · on the road · 2021-11-28 | 2021 | +3 | +34.0 | 43% | — |
| 18 | Western Kentucky over Marshall 53–21 · on the road · 2021-11-27 | 2021 | +1.5 | +33.5 | 46% | — |
| 19 | Minnesota over Colorado 30–0 · on the road · 2021-09-18 | 2021 | +2.5 | +32.5 | 44% | — |
| 20 | #22Louisiana over Liberty 42–14 · on the road · 2021-11-20 | 2021 | +4.5 | +32.5 | 39% | — |
| 21 | Wyoming over Utah State 44–17 · on the road · 2021-11-21 | 2021 | +5.5 | +32.5 | 37% | — |
| 22 | Louisiana over App State 41–13 · at home · 2021-10-12 | 2021 | +4 | +32.0 | 40% | — |
| 23 | Kansas over Texas 57–56 · on the road · 2021-11-14 | 2021 | +31 | +32.0 | 3% | — |
| 24 | Stanford over #14USC 42–28 · on the road · 2021-09-12 | 2021 | +17.5 | +31.5 | 14% | 16 |
| 25 | Southern Miss over Louisiana Tech 35–19 · on the road · 2021-11-20 | 2021 | +15.5 | +31.5 | 17% | — |
| 26 | New Mexico over Wyoming 14–3 · on the road · 2021-10-23 | 2021 | +20 | +31.0 | 11% | — |
| 27 | Duquesne over Ohio 28–26 · on the road · 2021-09-11 | 2021 | +28.5 | +30.5 | 4% | — |
| 28 | Jacksonville State over Florida State 20–17 · on the road · 2021-09-12 | 2021 | +27.5 | +30.5 | 4% | — |
| 29 | Colorado State over Toledo 22–6 · on the road · 2021-09-18 | 2021 | +14.5 | +30.5 | 18% | — |
| 30 | North Texas over #15UTSA 45–23 · at home · 2021-11-27 | 2021 | +8.5 | +30.5 | 30% | 15 |
| 31 | Rice over UAB 30–24 · on the road · 2021-10-23 | 2021 | +24 | +30.0 | 7% | — |
| 32 | Boise State over #25Fresno State 40–14 · on the road · 2021-11-06 | 2021 | +4 | +30.0 | 40% | 5 |
| 33 | Washington State over Arizona State 34–21 · on the road · 2021-10-30 | 2021 | +16.5 | +29.5 | 15% | — |
| 34 | South Carolina over #10North Carolina 38–21 · neutral site · 2021-12-30 | 2021 | +12.5 | +29.5 | 22% | 20 |
| 35 | Oregon State over USC 45–27 · on the road · 2021-09-26 | 2021 | +11 | +29.0 | 25% | — |
| 36 | Akron over Bowling Green 35–20 · on the road · 2021-10-09 | 2021 | +14 | +29.0 | 19% | — |
| 37 | Montana over #20Washington 13–7 · on the road · 2021-09-05 | 2021 | +22.5 | +28.5 | 8% | 10 |
| 38 | Northern Arizona over Arizona 21–19 · on the road · 2021-09-19 | 2021 | +26.5 | +28.5 | 5% | — |
| 39 | Michigan State over #24Miami 38–17 · on the road · 2021-09-18 | 2021 | +7 | +28.0 | 33% | 6 |
| 40 | Purdue over #2Iowa 24–7 · on the road · 2021-10-16 | 2021 | +11 | +28.0 | 25% | 28 |
| 41 | Florida State over North Carolina 35–25 · on the road · 2021-10-09 | 2021 | +17.5 | +27.5 | 14% | — |
| 42 | Liberty over UAB 36–12 · on the road · 2021-10-02 | 2021 | +3 | +27.0 | 43% | — |
| 43 | Illinois over #7Penn State 20–18 · on the road · 2021-10-23 | 2021 | +24.5 | +26.5 | 6% | 23 |
| 44 | East Carolina over Tulane 52–29 · at home · 2021-10-02 | 2021 | +3 | +26.0 | 43% | — |
| 45 | Maryland over Rutgers 40–16 · on the road · 2021-11-27 | 2021 | +2 | +26.0 | 45% | — |
| 46 | San Diego State over Arizona 38–14 · on the road · 2021-09-12 | 2021 | +1.5 | +25.5 | 46% | — |
| 47 | Bowling Green over Buffalo 56–44 · on the road · 2021-10-30 | 2021 | +13.5 | +25.5 | 20% | — |
| 48 | Arkansas over #15Texas 40–21 · at home · 2021-09-11 | 2021 | +6 | +25.0 | 35% | 15 |
| 49 | UC Davis over Tulsa 19–17 · on the road · 2021-09-02 | 2021 | +22 | +24.0 | 8% | — |
| 50 | Wake Forest over Virginia 37–17 · on the road · 2021-09-24 | 2021 | +3.5 | +23.5 | 41% | — |
| 51 | UL Monroe over South Alabama 41–31 · at home · 2021-10-23 | 2021 | +13.5 | +23.5 | 20% | — |
| 52 | #4Alabama over #1Georgia 41–24 · neutral site · 2021-12-04 | 2021 | +6.5 | +23.5 | 34% | 3 |
| 53 | #14Michigan over Wisconsin 38–17 · on the road · 2021-10-02 | 2021 | +2 | +23.0 | 45% | — |
| 54 | Kansas State over Nevada 38–17 · at home · 2021-09-18 | 2021 | +1.5 | +22.5 | 46% | — |
| 55 | Washington State over California 21–6 · on the road · 2021-10-02 | 2021 | +7.5 | +22.5 | 32% | — |
| 56 | UTEP over Louisiana Tech 19–3 · at home · 2021-10-17 | 2021 | +6.5 | +22.5 | 34% | — |
| 57 | Illinois over Minnesota 14–6 · on the road · 2021-11-06 | 2021 | +14.5 | +22.5 | 18% | — |
| 58 | Syracuse over Ohio 29–9 · on the road · 2021-09-04 | 2021 | +2 | +22.0 | 45% | — |
| 59 | Ball State over Army 28–16 · at home · 2021-10-02 | 2021 | +10 | +22.0 | 27% | — |
| 60 | Arizona State over #20UCLA 42–23 · on the road · 2021-10-03 | 2021 | +3 | +22.0 | 43% | 10 |