1º de Agosto 5-7 Namungo FC *
| 25.02.2021 | Namungo FC | 1-3 | 1º de Agosto | |
| 21.02.2021 | 1º de Agosto | 2-6 | Namungo FC | |
AS SONIDEB 0-2 Coton Sport *
| 21.02.2021 | Coton Sport | 1-0 | AS SONIDEB | |
| 14.02.2021 | AS SONIDEB | 0-1 | Coton Sport | |
*CS Sfaxien 5-2 AS Kigali
| 20.02.2021 | AS Kigali | 1-1 | CS Sfaxien | |
| 13.02.2021 | CS Sfaxien | 4-1 | AS Kigali | |
*Al Ahli Benghazi 2-2 DC Motema Pembe
| 21.02.2021 | DC Motema Pembe | 1-1/p.7-8 | Al Ahli Benghazi | |
| 14.02.2021 | Al Ahli Benghazi | 1-1 | DC Motema Pembe | |
Asante Kotoko 1-2 ES Sétif *
| 21.02.2021 | ES Sétif | 0-0 | Asante Kotoko | |
| 14.02.2021 | Asante Kotoko | 1-2 | ES Sétif | |
FC Platinum (ZIM) 0-2 ASC Jaraaf *
| 21.02.2021 | ASC Jaraaf | 1-0 | FC Platinum (ZIM) | |
| 14.02.2021 | FC Platinum (ZIM) | 0-1 | ASC Jaraaf | |
Jwaneng Galaxy 0-4 Orlando Pirates *
| 21.02.2021 | Orlando Pirates | 1-0 | Jwaneng Galaxy | |
| 14.02.2021 | Jwaneng Galaxy | 0-3 | Orlando Pirates | |
Gor Mahia 2-3 Napsa Stars *
| 21.02.2021 | Napsa Stars | 2-2 | Gor Mahia | |
| 14.02.2021 | Gor Mahia | 0-1 | Napsa Stars | |
*Nkana FC 3-2 TAS Casablanca
| 21.02.2021 | TAS Casablanca | 2-1 | Nkana FC | |
| 14.02.2021 | Nkana FC | 2-0 | TAS Casablanca | |
RC Abidjan 0-4 Pyramids FC *
| 21.02.2021 | Pyramids FC | 2-0 | RC Abidjan | |
| 14.02.2021 | RC Abidjan | 0-2 | Pyramids FC | |
*Raja Casablanca 1-1 US Monastir
| 21.02.2021 | US Monastir | 1-0/p.5-6 | Raja Casablanca | |
| 14.02.2021 | Raja Casablanca | 1-0 | US Monastir | |
*Enyimba FC 1-1 Rivers United
| 21.02.2021 | Rivers United | 1-0/p.4-5 | Enyimba FC | |
| 14.02.2021 | Enyimba FC | 1-0 | Rivers United | |
Bouenguidi Sports 2-3 Salitas FC *
| 21.02.2021 | Salitas FC | 3-1 | Bouenguidi Sports | |
| 14.02.2021 | Bouenguidi Sports | 1-0 | Salitas FC | |
Stade Malien 2-2 JS Kabylie *
| 21.02.2021 | JS Kabylie | 1-0 | Stade Malien | |
| 14.02.2021 | Stade Malien | 2-1 | JS Kabylie | |
Young Buffaloes 1-4 Étoile Sahel Sousse *
| 23.02.2021 | Étoile Sahel Sousse | 2-0 | Young Buffaloes | |
| 14.02.2021 | Young Buffaloes | 1-2 | Étoile Sahel Sousse | |