1st(1st leg) AmaZulu FC - TP Mazembe 0:0 (0:0)
2nd (2nd leg) TP Mazembe - AmaZulu FC -:-
1st(1st leg): 15/10/2021 16:00 2nd (2nd leg): 23/10/2021
1st(1st leg) Tusker FC - Zamalek 0:1 (0:0)
2nd (2nd leg) Zamalek - Tusker FC -:-
1st(1st leg): 16/10/2021 13:00 2nd (2nd leg): 22/10/2021
1st(1st leg) APR FC - Étoile du Sahel 1:1 (1:1)
2nd (2nd leg) Étoile du Sahel - APR FC -:-
1st(1st leg): 16/10/2021 14:00 2nd (2nd leg): 23/10/2021
1st(1st leg) GD Sagrada Esperança - Royal Leopards 3:1 (1:0)
2nd (2nd leg) Royal Leopards - GD Sagrada Esperança -:-
1st(1st leg): 16/10/2021 15:00 2nd (2nd leg): 23/10/2021
1st(1st leg) ASEC Mimosas - CR Bélouizdad 3:1 (1:1)
2nd (2nd leg) CR Bélouizdad - ASEC Mimosas -:-
1st(1st leg): 16/10/2021 16:00 2nd (2nd leg): 24/10/2021
1st(1st leg) USGN - Al Ahly SC 1:1 (0:1)
2nd (2nd leg) Al Ahly SC - USGN -:-
1st(1st leg): 16/10/2021 16:30 2nd (2nd leg): 23/10/2021
1st(1st leg) Stade Malien - Horoya AC 0:1 (0:0)
2nd (2nd leg) Horoya AC - Stade Malien -:-
1st(1st leg): 16/10/2021 18:00 2nd (2nd leg): 24/10/2021
1st(1st leg) Al Merrikh SC - Zanaco FC 3:0 (0:0)
2nd (2nd leg) Zanaco FC - Al Merrikh SC -:-
1st(1st leg): 16/10/2021 18:00 2nd (2nd leg): 23/10/2021
1st(1st leg) Jwaneng Galaxy - Simba SC 0:2 (0:2)
2nd (2nd leg) Simba SC - Jwaneng Galaxy -:-
1st(1st leg): 17/10/2021 14:00 2nd (2nd leg): 24/10/2021
1st(1st leg) AS Maniema Union - Mamelodi Sundowns 2:2 (1:1)
2nd (2nd leg) Mamelodi Sundowns - AS Maniema Union -:-
1st(1st leg): 17/10/2021 15:00 2nd (2nd leg): 24/10/2021
1st(1st leg) AS Otôho - Petro Atlético 2:2 (0:0)
2nd (2nd leg) Petro Atlético - AS Otôho -:-
1st(1st leg): 17/10/2021 15:30 2nd (2nd leg): 23/10/2021
1st(1st leg) Hearts of Oak - Wydad AC 1:0 (1:0)
2nd (2nd leg) Wydad AC - Hearts of Oak -:-
1st(1st leg): 17/10/2021 16:00 2nd (2nd leg): 24/10/2021
1st(1st leg) LPRC Oilers - Raja Casablanca 0:2 (0:2)
2nd (2nd leg) Raja Casablanca - LPRC Oilers -:-
1st(1st leg): 17/10/2021 16:00 2nd (2nd leg): 23/10/2021
1st(1st leg) Rivers United - Al Hilal Omdurman 1:1 (0:1)
2nd (2nd leg) Al Hilal Omdurman - Rivers United -:-
1st(1st leg): 17/10/2021 16:00 2nd (2nd leg): 24/10/2021
1st(1st leg) FC Nouadhibou - ES Sétif 3:1 (0:1)
2nd (2nd leg) ES Sétif - FC Nouadhibou -:-
1st(1st leg): 17/10/2021 17:00 2nd (2nd leg): 24/10/2021
1st(1st leg) Al Ittihad Tripolis - Espérance de Tunis 0:0 (0:0)
2nd (2nd leg) Espérance de Tunis - Al Ittihad Tripolis -:-
1st(1st leg): 17/10/2021 18:00 2nd (2nd leg): 24/10/2021 17:00