*AmaZulu FC 1-1 TP Mazembe
| 15.10.2021 | AmaZulu FC | 0-0 | TP Mazembe | |
| 23.10.2021 | TP Mazembe | 1-1 | AmaZulu FC | |
Tusker FC 0-5 Zamalek SC *
| 16.10.2021 | Tusker FC | 0-1 | Zamalek SC | |
| 22.10.2021 | Zamalek SC | 4-0 | Tusker FC | |
APR FC 1-5 Étoile Sahel Sousse *
| 16.10.2021 | APR FC | 1-1 | Étoile Sahel Sousse | |
| 23.10.2021 | Étoile Sahel Sousse | 4-0 | APR FC | |
*Sagrada Esperanca 3-2 Royal Leopards
| 16.10.2021 | Sagrada Esperanca | 3-1 | Royal Leopards | |
| 23.10.2021 | Royal Leopards | 1-0 | Sagrada Esperanca | |
ASEC Mimosas 3-3 CR Belouizdad *
| 16.10.2021 | ASEC Mimosas | 3-1 | CR Belouizdad | |
| 24.10.2021 | CR Belouizdad | 2-0 | ASEC Mimosas | |
US GN 2-7 Al Ahly Cairo *
| 16.10.2021 | US GN | 1-1 | Al Ahly Cairo | |
| 23.10.2021 | Al Ahly Cairo | 6-1 | US GN | |
*Al Merreikh SC 4-2 ZANACO FC
| 16.10.2021 | Al Merreikh SC | 3-0 | ZANACO FC | |
| 23.10.2021 | ZANACO FC | 2-1 | Al Merreikh SC | |
Stade Malien 1-3 Horoya AC *
| 16.10.2021 | Stade Malien | 0-1 | Horoya AC | |
| 24.10.2021 | Horoya AC | 2-1 | Stade Malien | |
*Jwaneng Galaxy 3-3 Simba SC
| 17.10.2021 | Jwaneng Galaxy | 0-2 | Simba SC | |
| 24.10.2021 | Simba SC | 1-3 | Jwaneng Galaxy | |
AS Maniema Union 2-4 Mamelodi Sundowns *
| 17.10.2021 | AS Maniema Union | 2-2 | Mamelodi Sundowns | |
| 24.10.2021 | Mamelodi Sundowns | 2-0 | AS Maniema Union | |
AS Otôho 2-4 Petro Atlético Luanda *
| 17.10.2021 | AS Otôho | 2-2 | Petro Atlético Luanda | |
| 23.10.2021 | Petro Atlético Luanda | 2-0 | AS Otôho | |
Accra Hearts of Oak 2-6 Wydad Casablanca *
| 17.10.2021 | Accra Hearts of Oak | 1-0 | Wydad Casablanca | |
| 24.10.2021 | Wydad Casablanca | 6-1 | Accra Hearts of Oak | |
Rivers United 1-2 Al Hilal Omdurman *
| 17.10.2021 | Rivers United | 1-1 | Al Hilal Omdurman | |
| 24.10.2021 | Al Hilal Omdurman | 1-0 | Rivers United | |
LPRC Oilers 0-4 Raja Casablanca *
| 17.10.2021 | LPRC Oilers | 0-2 | Raja Casablanca | |
| 23.10.2021 | Raja Casablanca | 2-0 | LPRC Oilers | |
FC Nouadhibou 3-3 ES Sétif *
| 17.10.2021 | FC Nouadhibou | 3-1 | ES Sétif | |
| 24.10.2021 | ES Sétif | 2-0 | FC Nouadhibou | |
Al Ittihad Tripoli 0-1 Esperance ST *
| 17.10.2021 | Al Ittihad Tripoli | 0-0 | Esperance ST | |
| 24.10.2021 | Esperance ST | 1-0 | Al Ittihad Tripoli | |