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| H | AmaZulu FC | - | TP Mazembe | 0:0 (0:0) | ||
| R | TP Mazembe | - | AmaZulu FC | 1:1 (0:1) | ||
| H: 15.10.2021 17:00 | R: 23.10.2021 15:00 | Sieger: AmaZulu FC | ||||
| H | Tusker FC | - | Zamalek | 0:1 (0:0) | ||
| R | Zamalek | - | Tusker FC | 4:0 (2:0) | ||
| H: 16.10.2021 14:00 | R: 22.10.2021 19:00 | Sieger: Zamalek | ||||
| H | APR FC | - | Étoile du Sahel | 1:1 (1:1) | ||
| R | Étoile du Sahel | - | APR FC | 4:0 (1:0) | ||
| H: 16.10.2021 15:00 | R: 23.10.2021 15:00 | Sieger: Étoile du Sahel | ||||
| H | GD Sagrada Esperança | - | Royal Leopards | 3:1 (1:0) | ||
| R | Royal Leopards | - | GD Sagrada Esperança | 1:0 (0:0) | ||
| H: 16.10.2021 16:00 | R: 23.10.2021 15:00 | Sieger: GD Sagrada Esperança | ||||
| H | ASEC Mimosas | - | CR Bélouizdad | 3:1 (1:1) | ||
| R | CR Bélouizdad | - | ASEC Mimosas | 2:0 (1:0) | ||
| H: 16.10.2021 17:00 | R: 24.10.2021 20:00 | Sieger: CR Bélouizdad | ||||
| H | USGN | - | Al Ahly SC | 1:1 (0:1) | ||
| R | Al Ahly SC | - | USGN | 6:1 (2:1) | ||
| H: 16.10.2021 17:30 | R: 23.10.2021 18:00 | Sieger: Al Ahly SC | ||||
| H | Stade Malien | - | Horoya AC | 0:1 (0:0) | ||
| R | Horoya AC | - | Stade Malien | 2:1 (1:0) | ||
| H: 16.10.2021 19:00 | R: 24.10.2021 18:30 | Sieger: Horoya AC | ||||
| H | Al Merrikh SC | - | Zanaco FC | 3:0 (0:0) | ||
| R | Zanaco FC | - | Al Merrikh SC | 2:1 (1:1) | ||
| H: 16.10.2021 19:00 | R: 23.10.2021 15:00 | Sieger: Al Merrikh SC | ||||
| H | Jwaneng Galaxy | - | Simba SC | 0:2 (0:2) | ||
| R | Simba SC | - | Jwaneng Galaxy | 1:3 (1:0) | ||
| H: 17.10.2021 15:00 | R: 24.10.2021 15:00 | Sieger: Jwaneng Galaxy | ||||
| H | AS Maniema Union | - | Mamelodi Sundowns | 2:2 (1:1) | ||
| R | Mamelodi Sundowns | - | AS Maniema Union | 2:0 (1:0) | ||
| H: 17.10.2021 16:00 | R: 24.10.2021 16:00 | Sieger: Mamelodi Sundowns | ||||
| H | AS Otôho | - | Petro Atlético | 2:2 (0:0) | ||
| R | Petro Atlético | - | AS Otôho | 2:0 (1:0) | ||
| H: 17.10.2021 16:30 | R: 23.10.2021 17:00 | Sieger: Petro Atlético | ||||
| H | Hearts of Oak | - | Wydad AC | 1:0 (1:0) | ||
| R | Wydad AC | - | Hearts of Oak | 6:1 (4:0) | ||
| H: 17.10.2021 17:00 | R: 24.10.2021 21:00 | Sieger: Wydad AC | ||||
| H | LPRC Oilers | - | Raja Casablanca | 0:2 (0:2) | ||
| R | Raja Casablanca | - | LPRC Oilers | 2:0 (2:0) | ||
| H: 17.10.2021 17:00 | R: 23.10.2021 20:00 | Sieger: Raja Casablanca | ||||
| H | Rivers United | - | Al Hilal Omdurman | 1:1 (0:1) | ||
| R | Al Hilal Omdurman | - | Rivers United | 1:0 (1:0) | ||
| H: 17.10.2021 17:00 | R: 24.10.2021 19:00 | Sieger: Al Hilal Omdurman | ||||
| H | FC Nouadhibou | - | ES Sétif | 3:1 (0:1) | ||
| R | ES Sétif | - | FC Nouadhibou | 2:0 (1:0) | ||
| H: 17.10.2021 18:00 | R: 24.10.2021 19:00 | Sieger: ES Sétif | ||||
| H | Al Ittihad Tripolis | - | Espérance de Tunis | 0:0 (0:0) | ||
| R | Espérance de Tunis | - | Al Ittihad Tripolis | 1:0 (0:0) | ||
| H: 17.10.2021 19:00 | R: 24.10.2021 18:00 | Sieger: Espérance de Tunis | ||||
