| 1. Round | 18/07/2021 | Santa Fe | - | Deportivo Cali | 1:2 | ||||
| 2. Round | 25/07/2021 | Atlético Bucaramanga | - | Santa Fe | 4:3 |  |
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| 3. Round | 04/08/2021 | Santa Fe | - | Atlético Nacional | 0:1 | ||||
| 4. Round | 08/08/2021 | Millonarios | - | Santa Fe | 0:1 | ||||
| 5. Round | 17/08/2021 | Santa Fe | - | La Equidad | 0:2 | ||||
| 9. Round | 12/09/2021 | Santa Fe | - | Alianza Petrolera | 1:1 | ||||
| 10. Round | 20/09/2021 | Deportivo Pasto | - | Santa Fe | 0:1 | ||||
| 11. Round | 25/09/2021 | Santa Fe | - | Envigado FC | 3:1 | ||||
| 13. Round | 12/10/2021 | Patriotas FC | - | Santa Fe | 0:1 | ||||
| 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 | |
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| 17. Round | 02/11/2021 | Deportes Quindío | - | Santa Fe | 1:1 |  |
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| 20. Round | 21/11/2021 | Santa Fe | - | Águilas Doradas | 0:1 |
Colombia