| 1. Round | 10/07/2022 | La Equidad | - | Santa Fe | 2:2 |  |
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| 2. Round | 14/07/2022 | Águilas Doradas | - | Santa Fe | 2:2 | ||||
| 3. Round | 17/07/2022 | Santa Fe | - | Cortuluá | 1:0 | ||||
| 4. Round | 24/07/2022 | Atlético Junior | - | Santa Fe | 2:0 | ||||
| 5. Round | 03/08/2022 | Santa Fe | - | América de Cali | 1:1 | ||||
| 6. Round | 08/08/2022 | Deportivo Pereira | - | Santa Fe | 0:1 |  |
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| 7. Round | 13/08/2022 | Santa Fe | - | Deportes Tolima | 2:1 | ||||
| 8. Round | 21/08/2022 | Independiente Medellín | - | Santa Fe | 2:0 | ||||
| 9. Round | 27/08/2022 | Santa Fe | - | Patriotas FC | 2:1 | |
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| 10. Round | 04/09/2022 | Millonarios | - | Santa Fe | 2:0 | ||||
| 11. Round | 11/09/2022 | Santa Fe | - | Deportivo Pasto | 2:1 | ||||
| 14. Round | 25/09/2022 | Unión Magdalena | - | Santa Fe | 0:2 | ||||
| 13. Round | 30/09/2022 | Santa Fe | - | Atlético Nacional | 1:1 | ||||
| 15. Round | 03/10/2022 | Santa Fe | - | Envigado FC | 1:0 | ||||
| 17. Round | 06/10/2022 | Santa Fe | - | Millonarios | 3:2 | ||||
| 16. Round | 11/10/2022 | Alianza Petrolera | - | Santa Fe | 4:0 | ||||
| 18. Round | 17/10/2022 | Jaguares de Córdoba | - | Santa Fe | 2:1 | ||||
| 19. Round | 22/10/2022 | Santa Fe | - | Deportivo Cali | 1:0 | |
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| 20. Round | 30/10/2022 | Santa Fe | - | Once Caldas | 2:1 |
Uruguay