| 1. Round | 11/09/2021 | River Plate | - | Cerrito | 1:0 |  |
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| 2. Round | 19/09/2021 | Liverpool | - | River Plate | 3:1 | ||||
| 3. Round | 25/09/2021 | River Plate | - | Deportivo Maldonado | 1:2 | ||||
| 4. Round | 02/10/2021 | River Plate | - | Cerro Largo | 0:4 | ||||
| 6. Round | 16/10/2021 | River Plate | - | Sud América | 5:1 | ||||
| 7. Round | 20/10/2021 | Plaza Colonia | - | River Plate | 0:0 | ||||
| 9. Round | 30/10/2021 | Boston River | - | River Plate | 1:2 | ||||
| 10. Round | 03/11/2021 | River Plate | - | Montevideo Wanderers | 0:1 | ||||
| 11. Round | 06/11/2021 | Rentistas | - | River Plate | 1:0 | ||||
| 13. Round | 22/11/2021 | Montevideo City Torque | - | River Plate | 1:1 | ||||
| 15. Round | 04/12/2021 | Nacional | - | River Plate | 4:2 |
Uruguay
Italy