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| 1st(1st leg) | Express FC | - | Al Merrikh SC | 2:1 (1:1) | ||
| 2nd (2nd leg) | Al Merrikh SC | - | Express FC | 1:0 (0:0) | ||
| 1st(1st leg): 10/09/2021 14:00 | 2nd (2nd leg): 19/09/2021 18:00 | Winner: Al Merrikh SC | ||||
| 1st(1st leg) | AmaZulu FC | - | Big Bullets FC | 0:1 (0:1) | ||
| 2nd (2nd leg) | Big Bullets FC | - | AmaZulu FC | 1:3 (0:2) | ||
| 1st(1st leg): 10/09/2021 16:00 | 2nd (2nd leg): 18/09/2021 15:00 | Winner: AmaZulu FC | ||||
| 1st(1st leg) | CI Kamsar | - | Hearts of Oak | dnp | ||
| 2nd (2nd leg) | Hearts of Oak | - | CI Kamsar | 2:0 (0:0) | ||
| 1st(1st leg): 11/09/2021 | 2nd (2nd leg): 19/09/2021 16:00 | Winner: Hearts of Oak | ||||
| 1st(1st leg) | Jwaneng Galaxy | - | DFC 8ème | 2:0 (0:0) | ||
| 2nd (2nd leg) | DFC 8ème | - | Jwaneng Galaxy | 1:0 (0:0) | ||
| 1st(1st leg): 11/09/2021 14:00 | 2nd (2nd leg): 17/09/2021 14:00 | Winner: Jwaneng Galaxy | ||||
| 1st(1st leg) | UD Songo | - | AS Otôho | 1:0 (0:0) | ||
| 2nd (2nd leg) | AS Otôho | - | UD Songo | 4:3 (0:0, 1:0) pso | ||
| 1st(1st leg): 11/09/2021 14:00 | 2nd (2nd leg): 19/09/2021 15:30 | Winner: AS Otôho | ||||
| 1st(1st leg) | Royal Leopards | - | ZESCO United | 1:0 (0:0) | ||
| 2nd (2nd leg) | ZESCO United | - | Royal Leopards | 2:1 (1:1) | ||
| 1st(1st leg): 11/09/2021 14:00 | 2nd (2nd leg): 18/09/2021 14:00 | Winner: Royal Leopards | ||||
| 1st(1st leg) | AS Arta | - | Tusker FC | 1:1 (1:1) | ||
| 2nd (2nd leg) | Tusker FC | - | AS Arta | 3:0 (2:0) | ||
| 1st(1st leg): 11/09/2021 15:00 | 2nd (2nd leg): 18/09/2021 14:00 | Winner: Tusker FC | ||||
| 1st(1st leg) | GD Sagrada Esperança | - | FC Platinum | 0:0 (0:0) | ||
| 2nd (2nd leg) | FC Platinum | - | GD Sagrada Esperança | 4:5 (0:0, 0:0) pso | ||
| 1st(1st leg): 11/09/2021 15:00 | 2nd (2nd leg): 18/09/2021 14:00 | Winner: GD Sagrada Esperança | ||||
| 1st(1st leg) | AS Bouenguidi | - | AS Maniema Union | 1:1 (1:1) | ||
| 2nd (2nd leg) | AS Maniema Union | - | AS Bouenguidi | 2:0 (2:0) | ||
| 1st(1st leg): 11/09/2021 15:30 | 2nd (2nd leg): 19/09/2021 15:00 | Winner: AS Maniema Union | ||||
| 1st(1st leg) | AS Sonabel | - | Stade Malien | 0:1 (0:1) | ||
| 2nd (2nd leg) | Stade Malien | - | AS Sonabel | 3:0 (3:0) | ||
| 1st(1st leg): 11/09/2021 16:00 | 2nd (2nd leg): 17/09/2021 17:00 | Winner: Stade Malien | ||||
| 1st(1st leg) | USGN | - | Le Messager Ngozi | 1:1 (1:0) | ||
| 2nd (2nd leg) | Le Messager Ngozi | - | USGN | 0:1 (0:0) | ||
| 1st(1st leg): 11/09/2021 16:30 | 2nd (2nd leg): 17/09/2021 14:00 | Winner: USGN | ||||
| 1st(1st leg) | Loto FC | - | FC Nouadhibou | 1:1 (0:1) | ||
| 2nd (2nd leg) | FC Nouadhibou | - | Loto FC | 2:0 (0:0) | ||
| 1st(1st leg): 11/09/2021 17:00 | 2nd (2nd leg): 18/09/2021 18:00 | Winner: FC Nouadhibou | ||||
| 1st(1st leg) | Fortune FC | - | ES Sétif | 3:0 (1:0) | ||
| 2nd (2nd leg) | ES Sétif | - | Fortune FC | 5:4 (3:0, 2:0) pso | ||
| 1st(1st leg): 11/09/2021 17:00 | 2nd (2nd leg): 19/09/2021 21:00 | Winner: ES Sétif | ||||
| 1st(1st leg) | Teungueth FC | - | ASEC Mimosas | 0:1 (0:0) | ||
| 2nd (2nd leg) | ASEC Mimosas | - | Teungueth FC | 1:0 (0:0) | ||
| 1st(1st leg): 11/09/2021 18:00 | 2nd (2nd leg): 19/09/2021 18:00 | Winner: ASEC Mimosas | ||||
| 1st(1st leg) | KMKM | - | Al Ittihad Tripolis | 0:2 (0:1) | ||
| 2nd (2nd leg) | Al Ittihad Tripolis | - | KMKM | 2:0 (0:0) | ||
| 1st(1st leg): 12/09/2021 12:00 | 2nd (2nd leg): 19/09/2021 17:00 | Winner: Al Ittihad Tripolis | ||||
| 1st(1st leg) | Mogadishu City Club | - | APR FC | 0:0 (0:0) | ||
| 2nd (2nd leg) | APR FC | - | Mogadishu City Club | 2:1 (0:1) | ||
| 1st(1st leg): 12/09/2021 14:00 | 2nd (2nd leg): 19/09/2021 14:00 | Winner: APR FC | ||||
| 1st(1st leg) | Fasil Kenema SC | - | Al Hilal Omdurman | 2:2 (0:1) | ||
| 2nd (2nd leg) | Al Hilal Omdurman | - | Fasil Kenema SC | 1:1 (1:0) | ||
| 1st(1st leg): 12/09/2021 14:00 | 2nd (2nd leg): 19/09/2021 16:00 | Winner: Al Hilal Omdurman | ||||
| 1st(1st leg) | Young Africans | - | Rivers United | 0:1 (0:0) | ||
| 2nd (2nd leg) | Rivers United | - | Young Africans | 1:0 (0:0) | ||
| 1st(1st leg): 12/09/2021 15:00 | 2nd (2nd leg): 19/09/2021 16:00 | Winner: Rivers United | ||||
| 1st(1st leg) | Akwa United | - | CR Bélouizdad | 1:0 (0:0) | ||
| 2nd (2nd leg) | CR Bélouizdad | - | Akwa United | 2:0 (0:0) | ||
| 1st(1st leg): 12/09/2021 15:00 | 2nd (2nd leg): 19/09/2021 21:00 | Winner: CR Bélouizdad | ||||
| 1st(1st leg) | Fovu Club de Baham | - | Petro Atlético | 2:2 (1:2) | ||
| 2nd (2nd leg) | Petro Atlético | - | Fovu Club de Baham | 0:0 (0:0) | ||
| 1st(1st leg): 12/09/2021 15:30 | 2nd (2nd leg): 18/09/2021 16:00 | Winner: Petro Atlético | ||||
| 1st(1st leg) | FC Akonangui | - | Zanaco FC | 0:2 (0:2) | ||
| 2nd (2nd leg) | Zanaco FC | - | FC Akonangui | 1:0 (0:0) | ||
| 1st(1st leg): 12/09/2021 15:30 | 2nd (2nd leg): 18/09/2021 14:00 | Winner: Zanaco FC | ||||
| 1st(1st leg) | LPRC Oilers | - | ASKO Kara | 3:0 (1:0) | ||
| 2nd (2nd leg) | ASKO Kara | - | LPRC Oilers | 2:1 (1:0) | ||
| 1st(1st leg): 12/09/2021 16:30 | 2nd (2nd leg): 19/09/2021 16:30 | Winner: LPRC Oilers | ||||
