| 2021-09-23 19:00:4309/23/2021 | Hatton | 30 - 14 | East Lawrence | Eagle Stadium |
| 2021-09-24 19:00:0009/24/2021 | Russellville | 21 - 58 | Hartselle | J.P. Cain Stadium |
| 2021-09-24 19:00:0009/24/2021 | Mars Hill | 7 - 49 | Cullman | Cullman High School |
| 2021-09-24 19:00:0009/24/2021 | Leeds | 37 - 13 | West Morgan | Rebels Stadium |
| 2021-09-24 19:00:0009/24/2021 | Danville | 12 - 35 | Priceville | Bulldog Stadium |
| 2021-09-24 19:00:0009/24/2021 | Lee | 15 - 55 | James Clemens | Milton Frank Stadium |
| 2021-09-24 19:00:0009/24/2021 | Bob Jones | 21 - 42 | Auburn | Auburn High School |
| 2021-09-24 19:00:0009/24/2021 | Buckhorn | 48 - 24 | Mae Jemison | Louis Crews Stadium |
| 2021-09-24 19:00:0009/24/2021 | Lauderdale Co. | 33 - 8 | Rogers | Pirate Field |
| 2021-09-24 19:00:0009/24/2021 | Haleyville | 13 - 12 | Phil Campbell | Phil Campbell High School |
| 2021-09-24 19:00:0109/24/2021 | Lexington | 48 - 0 | Elkmont | Boss Hill Stadium |
| 2021-09-24 19:00:0309/24/2021 | Central-Florence | 47 - 13 | Sheffield | |
| 2021-09-24 19:00:0309/24/2021 | North Sand Mtn | 22 - 6 | Cedar Bluff | Cedar Bluff High School |
| 2021-09-24 19:00:0409/24/2021 | East Limestone | 28 - 31 | West Limestone | West Limestone High School |
| 2021-09-24 19:00:1009/24/2021 | Boaz | 35 - 21 | Albertville | Albertville High School |
| 2021-09-24 19:00:2109/24/2021 | Colbert Co. | 25 - 0 | Colbert Heights | Amos Mitchell Stadium |
| 2021-09-24 19:00:2709/24/2021 | Columbia | 8 - 41 | Tanner | Rip Swanner Stadium |
| 2021-09-24 19:00:2709/24/2021 | Valley Head | 20 - 42 | Ider | Wayne C. Hardiman Stadium |
| 2021-09-24 19:00:2909/24/2021 | Brewer | 13 - 49 | Arab | Arab High School |
| 2021-09-24 19:00:3409/24/2021 | Hackleburg | 24 - 51 | Hubbertville | |
| 2021-09-24 19:00:3609/24/2021 | Cold Springs | 7 - 49 | Falkville | Burl Vest Stadium |
| 2021-09-24 19:00:4009/24/2021 | Clements | 27 - 55 | Ardmore | Ardmore High School |
| 2021-09-24 19:00:4409/24/2021 | Shoals Christian | 14 - 61 | Whitesburg Christian | |
| 2021-09-24 19:00:4809/24/2021 | DAR | 28 - 58 | Pisgah | Sam Kenimer Stadium |
| 2021-09-24 19:00:5509/24/2021 | Decatur Heritage | 55 - 14 | Woodville | Woodville High School |
| 2021-09-24 19:00:5709/24/2021 | Westminster Christian | 23 - 20 | Lawrence Co. | Lawerence County High School |
