| 1. Round | 21/01/2022 | Santa Fe | - | La Equidad | 1:1 | ||||
| 2. Round | 25/01/2022 | Santa Fe | - | Águilas Doradas | 3:0 | ||||
| 3. Round | 29/01/2022 | Cortuluá | - | Santa Fe | 1:1 | ||||
| 4. Round | 03/02/2022 | Santa Fe | - | Atlético Junior | 2:1 |  |
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| 5. Round | 08/02/2022 | América de Cali | - | Santa Fe | 2:2 |  |
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| 6. Round | 13/02/2022 | Santa Fe | - | Deportivo Pereira | 1:2 | |
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| 7. Round | 16/02/2022 | Deportes Tolima | - | Santa Fe | 3:0 | |
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| 8. Round | 19/02/2022 | Santa Fe | - | Independiente Medellín | 1:0 | ||||
| 10. Round | 06/03/2022 | Santa Fe | - | Millonarios | 0:3 | ||||
| 12. Round | 22/03/2022 | Santa Fe | - | Atlético Bucaramanga | 3:1 | ||||
| 13. Round | 29/03/2022 | Atlético Nacional | - | Santa Fe | 2:1 | |
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| 17. Round | 25/04/2022 | Millonarios | - | Santa Fe | 2:1 | ||||
| 18. Round | 01/05/2022 | Santa Fe | - | Jaguares de Córdoba | 4:0 | |
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| 20. Round | 15/05/2022 | Once Caldas | - | Santa Fe | 2:2 |
Uruguay