| 4. Round | 08/08/2021 | Millonarios | - | Santa Fe | 0:1 | ||||
| 5. Round | 17/08/2021 | Santa Fe | - | La Equidad | 0:2 | ||||
| 7. Round | 30/08/2021 | Santa Fe | - | América de Cali | 1:1 | ||||
| 8. Round | 05/09/2021 | Independiente Medellín | - | Santa Fe | 0:0 | ||||
| 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 | ||||
| 17. Round | 02/11/2021 | Deportes Quindío | - | Santa Fe | 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