*Red Arrows FC 1-0 1º de Agosto
| 24.10.2021 | 1º de Agosto | 0-0 | Red Arrows FC | |
| 16.10.2021 | Red Arrows FC | 1-0 | 1º de Agosto | |
Ahli Marawi 1-6 Gor Mahia *
| 24.10.2021 | Gor Mahia | 3-0 W.O. | Ahli Marawi | |
| 15.10.2021 | Ahli Marawi | 1-3 | Gor Mahia | |
Biashara United FC 2-3 Al Ahli Tripoli *
| 23.10.2021 | Al Ahli Tripoli | 3-0 W.O. | Biashara United FC | |
| 15.10.2021 | Biashara United FC | 2-0 | Al Ahli Tripoli | |
AS Kigali 2-4 DC Motema Pembe *
| 24.10.2021 | DC Motema Pembe | 2-1 | AS Kigali | |
| 17.10.2021 | AS Kigali | 1-2 | DC Motema Pembe | |
*Marumo Gallants FC 3-2 AS Vita Club
| 22.10.2021 | AS Vita Club | 1-1 | Marumo Gallants FC | |
| 15.10.2021 | Marumo Gallants FC | 2-1 | AS Vita Club | |
*Binga FC 1-1 ASFA Yennega
| 23.10.2021 | ASFA Yennega | 0-1/p.6-7 | Binga FC | |
| 15.10.2021 | Binga FC | 0-1 | ASFA Yennega | |
Bayelsa United 1-4 CS Sfaxien *
| 23.10.2021 | CS Sfaxien | 4-0 | Bayelsa United | |
| 17.10.2021 | Bayelsa United | 1-0 | CS Sfaxien | |
CFF Analamanga 0-6 Interclube Luanda *
| 22.10.2021 | Interclube Luanda | 3-0 W.O. | CFF Analamanga | |
| 17.10.2021 | CFF Analamanga | 0-3 | Interclube Luanda | |
Orapa United 2-2 Coton Sport *
| 23.10.2021 | Coton Sport | 1-0 | Orapa United | |
| 16.10.2021 | Orapa United | 2-1 | Coton Sport | |
Diambars FC 0-4 Enyimba *
| 24.10.2021 | Enyimba | 3-0 | Diambars FC | |
| 16.10.2021 | Diambars FC | 0-1 | Enyimba | |
FAR Rabat 1-3 JS Kabylie *
| 24.10.2021 | JS Kabylie | 2-1 | FAR Rabat | |
| 16.10.2021 | FAR Rabat | 0-1 | JS Kabylie | |
ASAC Concorde 2-3 JS Saoura *
| 23.10.2021 | JS Saoura | 1-1 | ASAC Concorde | |
| 16.10.2021 | ASAC Concorde | 1-2 | JS Saoura | |
Diables Noirs 0-1 Orlando Pirates *
| 24.10.2021 | Orlando Pirates | 1-0 | Diables Noirs | |
| 15.10.2021 | Diables Noirs | 0-0 | Orlando Pirates | |
Azam FC 0-1 Pyramids FC *
| 23.10.2021 | Pyramids FC | 1-0 | Azam FC | |
| 16.10.2021 | Azam FC | 0-0 | Pyramids FC | |
URA Kampala 0-1 Al Masry *
| 23.10.2021 | Al Masry | 1-0 | URA Kampala | |
| 16.10.2021 | URA Kampala | 0-0 | Al Masry | |
US Ben Guerdane 0-5 Renaissance Berkane *
| 24.10.2021 | Renaissance Berkane | 4-0 | US Ben Guerdane | |
| 16.10.2021 | US Ben Guerdane | 0-1 | Renaissance Berkane | |