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| H | Young Buffaloes | - | AS Vita Club | 2:2 (1:0) | ||
| R | AS Vita Club | - | Young Buffaloes | 4:1 (1:0) | ||
| H: 22.12.2020 14:00 | R: 06.01.2021 15:30 | Sieger: AS Vita Club | ||||
| H | Jwaneng Galaxy | - | Mamelodi Sundowns | 0:2 (0:1) | ||
| R | Mamelodi Sundowns | - | Jwaneng Galaxy | 3:1 (1:0) | ||
| H: 22.12.2020 14:30 | R: 05.01.2021 15:30 | Sieger: Mamelodi Sundowns | ||||
| H | Teungueth FC | - | Raja Casablanca | 0:0 (0:0) | ||
| R | Raja Casablanca | - | Teungueth FC | 1:3 (0:0, 0:0) i.E. | ||
| H: 22.12.2020 18:00 | R: 05.01.2021 19:00 | Sieger: Teungueth FC | ||||
| H | Gazelle FC | - | Zamalek | n.gesp. | ||
| R | Zamalek | - | Gazelle FC | n.gesp. | ||
| H: 23.12.2020 | R: 06.01.2021 | Sieger: Gazelle FC | ||||
| H | Al Merrikh SC | - | Enyimba Aba | 3:0 (2:0) | ||
| R | Enyimba Aba | - | Al Merrikh SC | 2:1 (1:1) | ||
| H: 23.12.2020 14:00 | R: 06.01.2021 15:30 | Sieger: Al Merrikh SC | ||||
| H | Nkana FC | - | Petro Atlético | 1:1 (0:0) | ||
| R | Petro Atlético | - | Nkana FC | 1:0 (0:0) | ||
| H: 23.12.2020 14:00 | R: 06.01.2021 17:00 | Sieger: Petro Atlético | ||||
| H | FC Platinum | - | Simba SC | 1:0 (1:0) | ||
| R | Simba SC | - | FC Platinum | 4:0 (1:0) | ||
| H: 23.12.2020 14:00 | R: 06.01.2021 15:00 | Sieger: Simba SC | ||||
| H | AS SONIDEP | - | Al Ahly SC | 0:1 (0:1) | ||
| R | Al Ahly SC | - | AS SONIDEP | 4:0 (2:0) | ||
| H: 23.12.2020 15:00 | R: 05.01.2021 18:00 | Sieger: Al Ahly SC | ||||
| H | AS Bouenguidi | - | TP Mazembe | 1:2 (1:1) | ||
| R | TP Mazembe | - | AS Bouenguidi | 2:1 (2:0) | ||
| H: 23.12.2020 15:30 | R: 06.01.2021 14:30 | Sieger: TP Mazembe | ||||
| H | Asante Kotoko | - | Al Hilal Omdurman | 0:1 (0:0) | ||
| R | Al Hilal Omdurman | - | Asante Kotoko | 2:0 Wert. | ||
| H: 23.12.2020 16:00 | R: 06.01.2021 14:00 | Sieger: Al Hilal Omdurman | ||||
| H | Stade Malien | - | Wydad AC | 1:0 (0:0) | ||
| R | Wydad AC | - | Stade Malien | 3:0 (1:0) | ||
| H: 23.12.2020 17:00 | R: 06.01.2021 17:00 | Sieger: Wydad AC | ||||
| H | RC Abidjan | - | Horoya AC | 1:1 (0:1) | ||
| R | Horoya AC | - | RC Abidjan | 1:0 (0:0) | ||
| H: 23.12.2020 17:00 | R: 06.01.2021 17:00 | Sieger: Horoya AC | ||||
| H | Al Ahly Benghazi | - | Espérance de Tunis | 0:0 (0:0) | ||
| R | Espérance de Tunis | - | Al Ahly Benghazi | 3:2 (1:0) | ||
| H: 23.12.2020 17:00 | R: 06.01.2021 15:00 | Sieger: Espérance de Tunis | ||||
| H | Kaizer Chiefs | - | CD 1º de Agosto | 0:0 (0:0) | ||
| R | CD 1º de Agosto | - | Kaizer Chiefs | 0:1 (0:1) | ||
| H: 23.12.2020 17:00 | R: 05.01.2021 16:00 | Sieger: Kaizer Chiefs | ||||
| H | CR Bélouizdad | - | Gor Mahia FC | 6:0 (4:0) | ||
| R | Gor Mahia FC | - | CR Bélouizdad | 1:2 (1:0) | ||
| H: 26.12.2020 20:45 | R: 06.01.2021 13:00 | Sieger: CR Bélouizdad | ||||
| H | MC Alger | - | CS Sfaxien | 2:0 (2:0) | ||
| R | CS Sfaxien | - | MC Alger | 1:0 (1:0) | ||
| H: 28.12.2020 20:45 | R: 06.01.2021 15:00 | Sieger: MC Alger | ||||
