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| U | Express FC | - | Al Merrikh SC | 2:1 (1:1) | ||
| R | Al Merrikh SC | - | Express FC | 1:0 (0:0) | ||
| U: 10.09.2021 15:00 | R: 19.09.2021 19:00 | Winnaars: Al Merrikh SC | ||||
| U | AmaZulu FC | - | Big Bullets FC | 0:1 (0:1) | ||
| R | Big Bullets FC | - | AmaZulu FC | 1:3 (0:2) | ||
| U: 10.09.2021 17:00 | R: 18.09.2021 16:00 | Winnaars: AmaZulu FC | ||||
| U | CI Kamsar | - | Hearts of Oak | niet gespeeld | ||
| R | Hearts of Oak | - | CI Kamsar | 2:0 (0:0) | ||
| U: 11.09.2021 | R: 19.09.2021 17:00 | Winnaars: Hearts of Oak | ||||
| U | Jwaneng Galaxy | - | DFC 8ème | 2:0 (0:0) | ||
| R | DFC 8ème | - | Jwaneng Galaxy | 1:0 (0:0) | ||
| U: 11.09.2021 15:00 | R: 17.09.2021 15:00 | Winnaars: Jwaneng Galaxy | ||||
| U | UD Songo | - | AS Otôho | 1:0 (0:0) | ||
| R | AS Otôho | - | UD Songo | 4:3 (0:0, 1:0) d.p. | ||
| U: 11.09.2021 15:00 | R: 19.09.2021 16:30 | Winnaars: AS Otôho | ||||
| U | Royal Leopards | - | ZESCO United | 1:0 (0:0) | ||
| R | ZESCO United | - | Royal Leopards | 2:1 (1:1) | ||
| U: 11.09.2021 15:00 | R: 18.09.2021 15:00 | Winnaars: Royal Leopards | ||||
| U | AS Arta | - | Tusker FC | 1:1 (1:1) | ||
| R | Tusker FC | - | AS Arta | 3:0 (2:0) | ||
| U: 11.09.2021 16:00 | R: 18.09.2021 15:00 | Winnaars: Tusker FC | ||||
| U | GD Sagrada Esperança | - | FC Platinum | 0:0 (0:0) | ||
| R | FC Platinum | - | GD Sagrada Esperança | 4:5 (0:0, 0:0) d.p. | ||
| U: 11.09.2021 16:00 | R: 18.09.2021 15:00 | Winnaars: GD Sagrada Esperança | ||||
| U | AS Bouenguidi | - | AS Maniema Union | 1:1 (1:1) | ||
| R | AS Maniema Union | - | AS Bouenguidi | 2:0 (2:0) | ||
| U: 11.09.2021 16:30 | R: 19.09.2021 16:00 | Winnaars: AS Maniema Union | ||||
| U | AS Sonabel | - | Stade Malien | 0:1 (0:1) | ||
| R | Stade Malien | - | AS Sonabel | 3:0 (3:0) | ||
| U: 11.09.2021 17:00 | R: 17.09.2021 18:00 | Winnaars: Stade Malien | ||||
| U | USGN | - | Le Messager Ngozi | 1:1 (1:0) | ||
| R | Le Messager Ngozi | - | USGN | 0:1 (0:0) | ||
| U: 11.09.2021 17:30 | R: 17.09.2021 15:00 | Winnaars: USGN | ||||
| U | Loto FC | - | FC Nouadhibou | 1:1 (0:1) | ||
| R | FC Nouadhibou | - | Loto FC | 2:0 (0:0) | ||
| U: 11.09.2021 18:00 | R: 18.09.2021 19:00 | Winnaars: FC Nouadhibou | ||||
| U | Fortune FC | - | ES Sétif | 3:0 (1:0) | ||
| R | ES Sétif | - | Fortune FC | 5:4 (3:0, 2:0) d.p. | ||
| U: 11.09.2021 18:00 | R: 19.09.2021 22:00 | Winnaars: ES Sétif | ||||
| U | Teungueth FC | - | ASEC Mimosas | 0:1 (0:0) | ||
| R | ASEC Mimosas | - | Teungueth FC | 1:0 (0:0) | ||
| U: 11.09.2021 19:00 | R: 19.09.2021 19:00 | Winnaars: ASEC Mimosas | ||||
| U | KMKM | - | Al Ittihad Tripolis | 0:2 (0:1) | ||
| R | Al Ittihad Tripolis | - | KMKM | 2:0 (0:0) | ||
| U: 12.09.2021 13:00 | R: 19.09.2021 18:00 | Winnaars: Al Ittihad Tripolis | ||||
| U | Mogadishu City Club | - | APR FC | 0:0 (0:0) | ||
| R | APR FC | - | Mogadishu City Club | 2:1 (0:1) | ||
| U: 12.09.2021 15:00 | R: 19.09.2021 15:00 | Winnaars: APR FC | ||||
| U | Fasil Kenema SC | - | Al Hilal Omdurman | 2:2 (0:1) | ||
| R | Al Hilal Omdurman | - | Fasil Kenema SC | 1:1 (1:0) | ||
| U: 12.09.2021 15:00 | R: 19.09.2021 17:00 | Winnaars: Al Hilal Omdurman | ||||
| U | Young Africans | - | Rivers United | 0:1 (0:0) | ||
| R | Rivers United | - | Young Africans | 1:0 (0:0) | ||
| U: 12.09.2021 16:00 | R: 19.09.2021 17:00 | Winnaars: Rivers United | ||||
| U | Akwa United | - | CR Bélouizdad | 1:0 (0:0) | ||
| R | CR Bélouizdad | - | Akwa United | 2:0 (0:0) | ||
| U: 12.09.2021 16:00 | R: 19.09.2021 22:00 | Winnaars: CR Bélouizdad | ||||
| U | Fovu Club de Baham | - | Petro Atlético | 2:2 (1:2) | ||
| R | Petro Atlético | - | Fovu Club de Baham | 0:0 (0:0) | ||
| U: 12.09.2021 16:30 | R: 18.09.2021 17:00 | Winnaars: Petro Atlético | ||||
| U | FC Akonangui | - | Zanaco FC | 0:2 (0:2) | ||
| R | Zanaco FC | - | FC Akonangui | 1:0 (0:0) | ||
| U: 12.09.2021 16:30 | R: 18.09.2021 15:00 | Winnaars: Zanaco FC | ||||
| U | LPRC Oilers | - | ASKO Kara | 3:0 (1:0) | ||
| R | ASKO Kara | - | LPRC Oilers | 2:1 (1:0) | ||
| U: 12.09.2021 17:30 | R: 19.09.2021 17:30 | Winnaars: LPRC Oilers | ||||
