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