| 2021-10-21 19:00:0010/21/2021 |  Brooks | 0 - 47 | Wilson  | Ralph Thompson Stadium |
| 2021-10-21 19:00:0010/21/2021 |  West Limestone | 50 - 56 | Priceville  | Bulldog Stadium |
| 2021-10-21 19:00:3510/21/2021 | Lee | 14 - 49 | Russellville  | Tigers Stadium |
| 2021-10-22 19:00:0010/22/2021 |  Buckhorn | 20 - 65 | Hartselle  | J.P. Cain Stadium |
| 2021-10-22 19:00:0010/22/2021 |  Cullman | 7 - 42 | Muscle Shoals  | |
| 2021-10-22 19:00:0010/22/2021 |  West Morgan | 20 - 23 | Rogers  | Pirate Field |
| 2021-10-22 19:00:0010/22/2021 |  Albertville | 10 - 62 | James Clemens  | |
| 2021-10-22 19:00:0010/22/2021 |  Florence | 62 - 6 | Grissom  | Milton Frank Stadium |
| 2021-10-22 19:00:0310/22/2021 |  Whitesburg Christian | 7 - 42 | Ider  | Wayne C. Hardiman Stadium |
| 2021-10-22 19:00:0410/22/2021 |  Columbia | 0 - 47 | Hazel Green  | Bob Grimwood Stadium |
| 2021-10-22 19:00:0710/22/2021 |  East Lawrence | 8 - 27 | Colbert Heights  | Amos Mitchell Stadium |
| 2021-10-22 19:00:0810/22/2021 |  Mae Jemison | 12 - 15 | Ardmore  | Ardmore High School |
| 2021-10-22 19:00:0910/22/2021 | Hubbard | 46 - 0 | Shoals Christian  | Flame Field |
| 2021-10-22 19:00:1810/22/2021 | Sylvania | 35 - 21 | East Limestone  | East Limestone Stadium |
| 2021-10-22 19:00:2110/22/2021 |  Hanceville | 14 - 24 | Section  | Section Stadium |
| 2021-10-22 19:00:2310/22/2021 |  Deshler | 28 - 42 | Central-Florence  | Wildcats Stadium |
| 2021-10-22 19:00:2510/22/2021 |  Decatur | 56 - 34 | Athens  | Golden Eagle Stadium |
| 2021-10-22 19:00:3610/22/2021 |  North Sand Mtn | 29 - 14 | Falkville  | Burl Vest Stadium |
| 2021-10-22 19:00:4310/22/2021 |  Tanner | 13 - 14 | Pisgah  | Sam Kenimer Stadium |
| 2021-10-22 19:00:5010/22/2021 |  Lawrence Co. | 6 - 35 | Brewer  | James Tucker Stadium |
| 2021-10-22 19:00:5610/22/2021 |  Decatur Heritage | 53 - 28 | Hackleburg  | Hackleburg High School |
| 2021-10-22 19:00:5710/22/2021 |  Danville | 28 - 40 | Phil Campbell  | Phil Campbell High School |
