| 1. Round | 13/09/2021 | Progreso | - | Villa Española | 1:1 | ||||
| 2. Round | 18/09/2021 | Villa Española | - | Sud América | 1:2 | ||||
| 3. Round | 24/09/2021 | Plaza Colonia | - | Villa Española | 4:0 | ||||
| 4. Round | 02/10/2021 | Villa Española | - | Fénix | 1:2 | ||||
| 5. Round | 10/10/2021 | Boston River | - | Villa Española | 1:0 | ||||
| 6. Round | 17/10/2021 | Villa Española | - | Montevideo Wanderers | 2:2 |  |
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| 7. Round | 20/10/2021 | Rentistas | - | Villa Española | 3:1 | ||||
| 8. Round | 23/10/2021 | Villa Española | - | Peñarol | 1:3 |  |
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| 10. Round | 02/11/2021 | Deportivo Maldonado | - | Villa Española | 0:1 | ||||
| 12. Round | 13/11/2021 | Cerrito | - | Villa Española | 1:0 | ||||
| 13. Round | 19/11/2021 | Villa Española | - | Liverpool | 0:3 | ||||
| 14. Round | 30/11/2021 | River Plate | - | Villa Española | 4:2 | ||||
| 15. Round | 05/12/2021 | Villa Española | - | Cerro Largo | 1:1 |
Uruguay