| 1. Round | 18/07/2021 | Santa Fe | - | Deportivo Cali | 1:2 |  |
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| 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 | |
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| 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 | ||||
| 10. Round | 20/09/2021 | Deportivo Pasto | - | Santa Fe | 0:1 | ||||
| 11. Round | 25/09/2021 | Santa Fe | - | Envigado FC | 3:1 | |
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| 12. Round | 02/10/2021 | Deportes Tolima | - | Santa Fe | 0:0 | ||||
| 13. Round | 12/10/2021 | Patriotas FC | - | Santa Fe | 0:1 | ||||
| 14. Round | 18/10/2021 | Santa Fe | - | Millonarios | 0:2 | |
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| 15. Round | 25/10/2021 | Atlético Huila | - | Santa Fe | 1:2 | |
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| 17. Round | 02/11/2021 | Deportes Quindío | - | Santa Fe | 1:1 | ||||
| 18. Round | 07/11/2021 | Santa Fe | - | Atlético Junior | 1:1 | ||||
| 19. Round | 16/11/2021 | Once Caldas | - | Santa Fe | 2:1 | ||||
| 20. Round | 21/11/2021 | Santa Fe | - | Águilas Doradas | 0:1 |
Colombia