*AmaZulu FC 3-2 Nyasa Big Bullets
| 18.09.2021 | Nyasa Big Bullets | 1-3 | AmaZulu FC | |
| 10.09.2021 | AmaZulu FC | 0-1 | Nyasa Big Bullets | |
Bouenguidi Sports 1-3 AS Maniema Union *
| 19.09.2021 | AS Maniema Union | 2-0 | Bouenguidi Sports | |
| 11.09.2021 | Bouenguidi Sports | 1-1 | AS Maniema Union | |
*LPRC Oilers 4-2 ASKO Kara
| 19.09.2021 | ASKO Kara | 2-1 | LPRC Oilers | |
| 12.09.2021 | LPRC Oilers | 3-0 | ASKO Kara | |
CI Kamsar 0-2 Accra Hearts of Oak *
| 19.09.2021 | Accra Hearts of Oak | 2-0 | CI Kamsar | |
| 12.09.2021 | CI Kamsar | CANC | Accra Hearts of Oak | |
Akwa United 1-2 CR Belouizdad *
| 19.09.2021 | CR Belouizdad | 2-0 | Akwa United | |
| 12.09.2021 | Akwa United | 1-0 | CR Belouizdad | |
*Jwaneng Galaxy 2-1 Diplomates FC 8ème Arr.
| 17.09.2021 | Diplomates FC 8ème Arr. | 1-0 | Jwaneng Galaxy | |
| 11.09.2021 | Jwaneng Galaxy | 2-0 | Diplomates FC 8ème Arr. | |
Express FC 2-2 Al Merreikh SC *
| 19.09.2021 | Al Merreikh SC | 1-0 | Express FC | |
| 10.09.2021 | Express FC | 2-1 | Al Merreikh SC | |
Fasil Kenema 3-3 Al Hilal Omdurman *
| 19.09.2021 | Al Hilal Omdurman | 1-1 | Fasil Kenema | |
| 12.09.2021 | Fasil Kenema | 2-2 | Al Hilal Omdurman | |
ESAE FC 1-3 FC Nouadhibou *
| 18.09.2021 | FC Nouadhibou | 2-0 | ESAE FC | |
| 11.09.2021 | ESAE FC | 1-1 | FC Nouadhibou | |
Fortune Football Club 3-3 ES Sétif *
| 19.09.2021 | ES Sétif | 3-0/p.5-4 | Fortune Football Club | |
| 11.09.2021 | Fortune Football Club | 3-0 | ES Sétif | |
Fovu Baham 2-2 Petro Atlético Luanda *
| 18.09.2021 | Petro Atlético Luanda | 0-0 | Fovu Baham | |
| 12.09.2021 | Fovu Baham | 2-2 | Petro Atlético Luanda | |
KMKM 0-4 Ittihad Tripoli *
| 19.09.2021 | Ittihad Tripoli | 2-0 | KMKM | |
| 12.09.2021 | KMKM | 0-2 | Ittihad Tripoli | |
*US GN 2-1 Le Messager Ngozi
| 17.09.2021 | Le Messager Ngozi | 0-1 | US GN | |
| 11.09.2021 | US GN | 1-1 | Le Messager Ngozi | |
Mogadishu City 1-2 APR FC *
| 19.09.2021 | APR FC | 2-1 | Mogadishu City | |
| 12.09.2021 | Mogadishu City | 0-0 | APR FC | |
*Sagrada Esperanca 0-0 FC Platinum (ZIM)
| 18.09.2021 | FC Platinum (ZIM) | 0-0/p.4-5 | Sagrada Esperanca | |
| 11.09.2021 | Sagrada Esperanca | 0-0 | FC Platinum (ZIM) | |
AS Sonabel 0-4 Stade Malien *
| 17.09.2021 | Stade Malien | 3-0 | AS Sonabel | |
| 11.09.2021 | AS Sonabel | 0-1 | Stade Malien | |
Teungueth FC 0-2 ASEC Mimosas *
| 19.09.2021 | ASEC Mimosas | 1-0 | Teungueth FC | |
| 11.09.2021 | Teungueth FC | 0-1 | ASEC Mimosas | |
Young Africans 0-2 Rivers United *
| 19.09.2021 | Rivers United | 1-0 | Young Africans | |
| 12.09.2021 | Young Africans | 0-1 | Rivers United | |
*Royal Leopards 2-2 ZESCO United
| 18.09.2021 | ZESCO United | 2-1 | Royal Leopards | |
| 11.09.2021 | Royal Leopards | 1-0 | ZESCO United | |