Accra Hearts of Oak 2-4 JS Saoura *
| 05.12.2021 | JS Saoura | 4-0 | Accra Hearts of Oak | |
| 28.11.2021 | Accra Hearts of Oak | 2-0 | JS Saoura | |
Rivers United 2-2 Al Masry *
| 05.12.2021 | Al Masry | 1-0 | Rivers United | |
| 28.11.2021 | Rivers United | 2-1 | Al Masry | |
*ASEC Mimosas 5-2 Interclube Luanda
| 05.12.2021 | Interclube Luanda | 2-3 | ASEC Mimosas | |
| 28.11.2021 | ASEC Mimosas | 2-0 | Interclube Luanda | |
*US GN 2-1 DC Motema Pembe
| 05.12.2021 | DC Motema Pembe | 1-0 | US GN | |
| 28.11.2021 | US GN | 2-0 | DC Motema Pembe | |
FC Nouadhibou 0-2 Coton Sport *
| 05.12.2021 | Coton Sport | 2-0 | FC Nouadhibou | |
| 28.11.2021 | FC Nouadhibou | 0-0 | Coton Sport | |
Enyimba 2-3 Ittihad Tripoli *
| 19.12.2021 | Ittihad Tripoli | 3-0 W.O. | Enyimba | |
| 05.12.2021 | Enyimba | 2-0 | Ittihad Tripoli | |
LPRC Oilers 0-5 Orlando Pirates *
| 05.12.2021 | Orlando Pirates | 3-0 W.O. | LPRC Oilers | |
| 28.11.2021 | LPRC Oilers | 0-2 | Orlando Pirates | |
*TP Mazembe 1-0 Marumo Gallants FC
| 05.12.2021 | Marumo Gallants FC | 0-0 | TP Mazembe | |
| 28.11.2021 | TP Mazembe | 1-0 | Marumo Gallants FC | |
AS Maniema Union 0-2 Pyramids FC *
| 05.12.2021 | Pyramids FC | 1-0 | AS Maniema Union | |
| 28.11.2021 | AS Maniema Union | 0-1 | Pyramids FC | |
*Simba SC 4-2 Red Arrows FC
| 05.12.2021 | Red Arrows FC | 2-1 | Simba SC | |
| 28.11.2021 | Simba SC | 3-0 | Red Arrows FC | |
APR FC 1-2 Renaissance Berkane *
| 05.12.2021 | Renaissance Berkane | 2-1 | APR FC | |
| 28.11.2021 | APR FC | 0-0 | Renaissance Berkane | |
*Royal Leopards 2-2 JS Kabylie
| 06.02.2022 | JS Kabylie | 2-1 | Royal Leopards | |
| 28.11.2021 | Royal Leopards | 1-0 | JS Kabylie | |
Stade Malien 1-1 Al Ahli Tripoli *
| 05.12.2021 | Al Ahli Tripoli | 1-0/p.4-2 | Stade Malien | |
| 28.11.2021 | Stade Malien | 1-0 | Al Ahli Tripoli | |
Tusker FC 0-1 CS Sfaxien *
| 05.12.2021 | CS Sfaxien | 1-0 | Tusker FC | |
| 28.11.2021 | Tusker FC | 0-0 | CS Sfaxien | |