| 1. Round | 18/07/2021 | Santa Fe | - | Deportivo Cali | 1:2 | ||||
| 2. Round | 25/07/2021 | Atlético Bucaramanga | - | Santa Fe | 4:3 | ||||
| 3. Round | 04/08/2021 | Santa Fe | - | Atlético Nacional | 0:1 | ||||
| 5. Round | 17/08/2021 | Santa Fe | - | La Equidad | 0:2 | ||||
| 6. Round | 21/08/2021 | Deportivo Pereira | - | Santa Fe | 1:1 |  |
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| 7. Round | 30/08/2021 | Santa Fe | - | América de Cali | 1:1 | ||||
| 8. Round | 05/09/2021 | Independiente Medellín | - | Santa Fe | 0:0 | ||||
| 9. Round | 12/09/2021 | Santa Fe | - | Alianza Petrolera | 1:1 | ||||
| 11. Round | 25/09/2021 | Santa Fe | - | Envigado FC | 3:1 | ||||
| 12. Round | 02/10/2021 | Deportes Tolima | - | Santa Fe | 0:0 | ||||
| 14. Round | 18/10/2021 | Santa Fe | - | Millonarios | 0:2 | ||||
| 15. Round | 25/10/2021 | Atlético Huila | - | Santa Fe | 1:2 | ||||
| 16. Round | 28/10/2021 | Santa Fe | - | Jaguares de Córdoba | 3:1 | ||||
| 18. Round | 07/11/2021 | Santa Fe | - | Atlético Junior | 1:1 | |
Colombia