| 18. Round | 14/09/2021 | Always Ready | - | Real Santa Cruz | 4:0 | ||||
| 20. Round | 22/09/2021 | Real Potosí | - | Real Santa Cruz | 3:0 | ||||
| 21. Round | 27/09/2021 | Real Santa Cruz | - | CD Guabirá | 3:0 | ||||
| 22. Round | 18/10/2021 | Blooming | - | Real Santa Cruz | 3:1 |  |
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| 23. Round | 25/10/2021 | Real Santa Cruz | - | Bolívar | 0:3 | ||||
| 25. Round | 01/11/2021 | Real Santa Cruz | - | Real Tomayapo | 2:0 | |
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| 24. Round | 07/11/2021 | Club Aurora | - | Real Santa Cruz | 4:1 | ||||
| 26. Round | 22/11/2021 | Club San José | - | Real Santa Cruz | 1:2 | ||||
| 27. Round | 27/11/2021 | Independiente Petrolero | - | Real Santa Cruz | 2:1 | ||||
| 28. Round | 01/12/2021 | Real Santa Cruz | - | Nacional Potosí | 1:1 | ||||
| 29. Round | 05/12/2021 | Oriente Petrolero | - | Real Santa Cruz | 2:0 | ||||
| 30. Round | 12/12/2021 | Real Santa Cruz | - | The Strongest | 1:0 |
Haiti