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| 1st(1st leg) | LDU Quito | - | Grêmio Porto Alegre | 0:1 (0:1) | ||
| 2nd (2nd leg) | Grêmio Porto Alegre | - | LDU Quito | 1:2 (1:1) | ||
| 1st(1st leg): 13/07/2021 23:15 | 2nd (2nd leg): 20/07/2021 23:15 | Winner: LDU Quito | ||||
| 1st(1st leg) | América de Cali | - | Athletico Paranaense | 0:1 (0:0) | ||
| 2nd (2nd leg) | Athletico Paranaense | - | América de Cali | 4:1 (1:0) | ||
| 1st(1st leg): 14/07/2021 01:30 | 2nd (2nd leg): 21/07/2021 01:30 | Winner: Athletico Paranaense | ||||
| 1st(1st leg) | Sporting Cristal | - | Arsenal de Sarandí | 2:1 (0:0) | ||
| 2nd (2nd leg) | Arsenal de Sarandí | - | Sporting Cristal | 1:1 (0:0) | ||
| 1st(1st leg): 14/07/2021 23:15 | 2nd (2nd leg): 21/07/2021 23:15 | Winner: Sporting Cristal | ||||
| 1st(1st leg) | Independiente del Valle | - | Red Bull Bragantino | 0:2 (0:1) | ||
| 2nd (2nd leg) | Red Bull Bragantino | - | Independiente del Valle | 1:1 (0:1) | ||
| 1st(1st leg): 15/07/2021 01:30 | 2nd (2nd leg): 22/07/2021 01:30 | Winner: Red Bull Bragantino | ||||
| 1st(1st leg) | Atlético Junior | - | Libertad | 3:4 (3:2) | ||
| 2nd (2nd leg) | Libertad | - | Atlético Junior | 0:1 (0:0) | ||
| 1st(1st leg): 15/07/2021 01:30 | 2nd (2nd leg): 22/07/2021 01:30 | Winner: Libertad | ||||
| 1st(1st leg) | Santos FC | - | Independiente | 1:0 (0:0) | ||
| 2nd (2nd leg) | Independiente | - | Santos FC | 1:1 (0:1) | ||
| 1st(1st leg): 15/07/2021 23:15 | 2nd (2nd leg): 22/07/2021 23:15 | Winner: Santos FC | ||||
| 1st(1st leg) | Nacional | - | Peñarol | 1:2 (0:1) | ||
| 2nd (2nd leg) | Peñarol | - | Nacional | 0:1 (0:0) | ||
| 1st(1st leg): 16/07/2021 01:30 | 2nd (2nd leg): 23/07/2021 01:30 | Winner: Peñarol | ||||
| 1st(1st leg) | Deportivo Táchira | - | Rosario Central | 2:2 (0:1) | ||
| 2nd (2nd leg) | Rosario Central | - | Deportivo Táchira | 1:0 (1:0) | ||
| 1st(1st leg): 16/07/2021 01:30 | 2nd (2nd leg): 23/07/2021 01:30 | Winner: Rosario Central | ||||
