1st(1st leg) Express FC - Al Merrikh SC 2:1 (1:1)
2nd (2nd leg) Al Merrikh SC - Express FC 1:0 (0:0)
1st(1st leg): 10/09/2021 14:00 2nd (2nd leg): 19/09/2021 18:00 Winner: Al Merrikh SC
1st(1st leg) AmaZulu FC - Big Bullets FC 0:1 (0:1)
2nd (2nd leg) Big Bullets FC - AmaZulu FC 1:3 (0:2)
1st(1st leg): 10/09/2021 16:00 2nd (2nd leg): 18/09/2021 15:00 Winner: AmaZulu FC
1st(1st leg) CI Kamsar - Hearts of Oak dnp
2nd (2nd leg) Hearts of Oak - CI Kamsar 2:0 (0:0)
1st(1st leg): 11/09/2021 2nd (2nd leg): 19/09/2021 16:00 Winner: Hearts of Oak
1st(1st leg) Jwaneng Galaxy - DFC 8ème 2:0 (0:0)
2nd (2nd leg) DFC 8ème - Jwaneng Galaxy 1:0 (0:0)
1st(1st leg): 11/09/2021 14:00 2nd (2nd leg): 17/09/2021 14:00 Winner: Jwaneng Galaxy
1st(1st leg) UD Songo - AS Otôho 1:0 (0:0)
2nd (2nd leg) AS Otôho - UD Songo 4:3 (0:0, 1:0) pso
1st(1st leg): 11/09/2021 14:00 2nd (2nd leg): 19/09/2021 15:30 Winner: AS Otôho
1st(1st leg) Royal Leopards - ZESCO United 1:0 (0:0)
2nd (2nd leg) ZESCO United - Royal Leopards 2:1 (1:1)
1st(1st leg): 11/09/2021 14:00 2nd (2nd leg): 18/09/2021 14:00 Winner: Royal Leopards
1st(1st leg) AS Arta - Tusker FC 1:1 (1:1)
2nd (2nd leg) Tusker FC - AS Arta 3:0 (2:0)
1st(1st leg): 11/09/2021 15:00 2nd (2nd leg): 18/09/2021 14:00 Winner: Tusker FC
1st(1st leg) GD Sagrada Esperança - FC Platinum 0:0 (0:0)
2nd (2nd leg) FC Platinum - GD Sagrada Esperança 4:5 (0:0, 0:0) pso
1st(1st leg): 11/09/2021 15:00 2nd (2nd leg): 18/09/2021 14:00 Winner: GD Sagrada Esperança
1st(1st leg) AS Bouenguidi - AS Maniema Union 1:1 (1:1)
2nd (2nd leg) AS Maniema Union - AS Bouenguidi 2:0 (2:0)
1st(1st leg): 11/09/2021 15:30 2nd (2nd leg): 19/09/2021 15:00 Winner: AS Maniema Union
1st(1st leg) AS Sonabel - Stade Malien 0:1 (0:1)
2nd (2nd leg) Stade Malien - AS Sonabel 3:0 (3:0)
1st(1st leg): 11/09/2021 16:00 2nd (2nd leg): 17/09/2021 17:00 Winner: Stade Malien
1st(1st leg) USGN - Le Messager Ngozi 1:1 (1:0)
2nd (2nd leg) Le Messager Ngozi - USGN 0:1 (0:0)
1st(1st leg): 11/09/2021 16:30 2nd (2nd leg): 17/09/2021 14:00 Winner: USGN
1st(1st leg) ESAE FC - FC Nouadhibou 1:1 (0:1)
2nd (2nd leg) FC Nouadhibou - ESAE FC 2:0 (0:0)
1st(1st leg): 11/09/2021 17:00 2nd (2nd leg): 18/09/2021 18:00 Winner: FC Nouadhibou
1st(1st leg) Fortune FC - ES Sétif 3:0 (1:0)
2nd (2nd leg) ES Sétif - Fortune FC 5:4 (3:0, 2:0) pso
1st(1st leg): 11/09/2021 17:00 2nd (2nd leg): 19/09/2021 21:00 Winner: ES Sétif
1st(1st leg) Teungueth FC - ASEC Mimosas 0:1 (0:0)
2nd (2nd leg) ASEC Mimosas - Teungueth FC 1:0 (0:0)
1st(1st leg): 11/09/2021 18:00 2nd (2nd leg): 19/09/2021 18:00 Winner: ASEC Mimosas
1st(1st leg) KMKM - Al Ittihad Tripolis 0:2 (0:1)
2nd (2nd leg) Al Ittihad Tripolis - KMKM 2:0 (0:0)
1st(1st leg): 12/09/2021 12:00 2nd (2nd leg): 19/09/2021 17:00 Winner: Al Ittihad Tripolis
1st(1st leg) Mogadishu City Club - APR FC 0:0 (0:0)
2nd (2nd leg) APR FC - Mogadishu City Club 2:1 (0:1)
1st(1st leg): 12/09/2021 14:00 2nd (2nd leg): 19/09/2021 14:00 Winner: APR FC
1st(1st leg) Fasil Kenema SC - Al Hilal Omdurman 2:2 (0:1)
2nd (2nd leg) Al Hilal Omdurman - Fasil Kenema SC 1:1 (1:0)
1st(1st leg): 12/09/2021 14:00 2nd (2nd leg): 19/09/2021 16:00 Winner: Al Hilal Omdurman
1st(1st leg) Young Africans - Rivers United 0:1 (0:0)
2nd (2nd leg) Rivers United - Young Africans 1:0 (0:0)
1st(1st leg): 12/09/2021 15:00 2nd (2nd leg): 19/09/2021 16:00 Winner: Rivers United
1st(1st leg) Akwa United - CR Bélouizdad 1:0 (0:0)
2nd (2nd leg) CR Bélouizdad - Akwa United 2:0 (0:0)
1st(1st leg): 12/09/2021 15:00 2nd (2nd leg): 19/09/2021 21:00 Winner: CR Bélouizdad
1st(1st leg) Fovu Club de Baham - Petro Atlético 2:2 (1:2)
2nd (2nd leg) Petro Atlético - Fovu Club de Baham 0:0 (0:0)
1st(1st leg): 12/09/2021 15:30 2nd (2nd leg): 18/09/2021 16:00 Winner: Petro Atlético
1st(1st leg) FC Akonangui - Zanaco FC 0:2 (0:2)
2nd (2nd leg) Zanaco FC - FC Akonangui 1:0 (0:0)
1st(1st leg): 12/09/2021 15:30 2nd (2nd leg): 18/09/2021 14:00 Winner: Zanaco FC
1st(1st leg) LPRC Oilers - ASKO Kara 3:0 (1:0)
2nd (2nd leg) ASKO Kara - LPRC Oilers 2:1 (1:0)
1st(1st leg): 12/09/2021 16:30 2nd (2nd leg): 19/09/2021 16:30 Winner: LPRC Oilers