| 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 | 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 |
