Atlabara Juba 0-4 Al Ahli Merowe *
| 17.09.2021 | Al Ahli Merowe | 2-0 | Atlabara Juba | |
| 11.09.2021 | Atlabara Juba | 0-2 | Al Ahli Merowe | |
Hay Al Wadi 0-4 Al Ahli Tripoli *
| 19.09.2021 | Al Ahli Tripoli | 4-0 | Hay Al Wadi | |
| 13.09.2021 | Hay Al Wadi | CANC | Al Ahli Tripoli | |
Olympique Missiri 1-8 AS Kigali *
| 18.09.2021 | AS Kigali | 6-0 | Olympique Missiri | |
| 10.09.2021 | Olympique Missiri | 1-2 | AS Kigali | |
*US Ben Guerdane 3-2 AS Police (NIG)
| 18.09.2021 | AS Police (NIG) | 1-0 | US Ben Guerdane | |
| 12.09.2021 | US Ben Guerdane | 3-1 | AS Police (NIG) | |
ASC Kara 3-4 ASAC Concorde *
| 19.09.2021 | ASAC Concorde | 4-0 | ASC Kara | |
| 12.09.2021 | ASC Kara | 3-0 | ASAC Concorde | |
*Bayelsa United 4-2 Ashanti Golden Boys
| 19.09.2021 | Ashanti Golden Boys | 2-4 | Bayelsa United | |
| 12.09.2021 | Bayelsa United | CANC | Ashanti Golden Boys | |
*Binga FC 5-0 Monrovia Club Breweries
| 19.09.2021 | Monrovia Club Breweries | 0-2 | Binga FC | |
| 11.09.2021 | Binga FC | 3-0 | Monrovia Club Breweries | |
*FAR Rabat 3-1 Buffles du Borgou
| 18.09.2021 | Buffles du Borgou | 0-0 | FAR Rabat | |
| 12.09.2021 | FAR Rabat | 3-1 | Buffles du Borgou | |
Bumamuru FC 0-1 Diables Noirs *
| 18.09.2021 | Diables Noirs | 1-0 | Bumamuru FC | |
| 10.09.2021 | Bumamuru FC | 0-0 | Diables Noirs | |
*CFF Analamanga 2-1 Kabwe Warriors
| 19.09.2021 | Kabwe Warriors | 1-2 | CFF Analamanga | |
| 12.09.2021 | CFF Analamanga | 0-0 | Kabwe Warriors | |
*URA FC 5-2 Ethiopian Coffee
| 19.09.2021 | Ethiopian Coffee | 1-3 | URA FC | |
| 12.09.2021 | URA FC | 2-1 | Ethiopian Coffee | |
FC Dikhil 0-3 Biashara United FC *
| 18.09.2021 | Biashara United FC | 2-0 | FC Dikhil | |
| 10.09.2021 | FC Dikhil | 0-1 | Biashara United FC | |
*ASFA Yennega 2-1 FC San Pédro
| 19.09.2021 | FC San Pédro | 1-2 | ASFA Yennega | |
| 12.09.2021 | ASFA Yennega | 0-0 | FC San Pédro | |
Futuro Kings 2-4 Marumo Gallants FC *
| 17.09.2021 | Marumo Gallants FC | 3-0 | Futuro Kings | |
| 11.09.2021 | Futuro Kings | 2-1 | Marumo Gallants FC | |
*Azam FC 4-1 Horseed FC
| 18.09.2021 | Horseed FC | 0-1 | Azam FC | |
| 11.09.2021 | Azam FC | 3-1 | Horseed FC | |
Mafunzo FC 0-4 Interclube Luanda *
| 19.09.2021 | Interclube Luanda | 3-0 | Mafunzo FC | |
| 12.09.2021 | Mafunzo FC | 0-1 | Interclube Luanda | |
AS Mangasport 0-0 Orapa United *
| 18.09.2021 | Orapa United | 0-0/p.3-2 | AS Mangasport | |
| 12.09.2021 | AS Mangasport | 0-0 | Orapa United | |
*Red Arrows FC 2-1 Young Buffaloes
| 18.09.2021 | Young Buffaloes | 0-0 | Red Arrows FC | |
| 11.09.2021 | Red Arrows FC | 2-1 | Young Buffaloes | |
*Diambars FC 3-0 Wakriya AC
| 19.09.2021 | Wakriya AC | CANC | Diambars FC | |
| 12.09.2021 | Diambars FC | 3-0 | Wakriya AC | |