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| 1st(1st leg) | Rosario Central | - | Red Bull Bragantino | 3:4 (1:3) | ||
| 2nd (2nd leg) | Red Bull Bragantino | - | Rosario Central | 1:0 (0:0) | ||
| 1st(1st leg): 10/08/2021 23:15 | 2nd (2nd leg): 17/08/2021 23:15 | Winner: Red Bull Bragantino | ||||
| 1st(1st leg) | Sporting Cristal | - | Peñarol | 1:3 (0:2) | ||
| 2nd (2nd leg) | Peñarol | - | Sporting Cristal | 1:0 (1:0) | ||
| 1st(1st leg): 11/08/2021 23:15 | 2nd (2nd leg): 18/08/2021 23:15 | Winner: Peñarol | ||||
| 1st(1st leg) | LDU Quito | - | Athletico Paranaense | 1:0 (0:0) | ||
| 2nd (2nd leg) | Athletico Paranaense | - | LDU Quito | 4:2 (2:2) | ||
| 1st(1st leg): 12/08/2021 23:15 | 2nd (2nd leg): 19/08/2021 23:15 | Winner: Athletico Paranaense | ||||
| 1st(1st leg) | Santos FC | - | Libertad | 2:1 (1:0) | ||
| 2nd (2nd leg) | Libertad | - | Santos FC | 1:0 (1:0) | ||
| 1st(1st leg): 13/08/2021 01:30 | 2nd (2nd leg): 20/08/2021 01:30 | Winner: Libertad | ||||
