| 4. Round | 07/08/2021 | Club Nacional | - | Libertad | 1:0 | ||||
| 5. Round | 14/08/2021 | River Plate | - | Club Nacional | 1:0 | ||||
| 6. Round | 21/08/2021 | Club Nacional | - | Guaireña FC | 0:2 | ||||
| 7. Round | 29/08/2021 | Cerro Porteño | - | Club Nacional | 0:2 |  |
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| 8. Round | 11/09/2021 | Club Nacional | - | Sol de América | 1:1 |  |
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| 9. Round | 21/09/2021 | Club Olimpia | - | Club Nacional | 1:2 | ||||
| 10. Round | 25/09/2021 | Club Nacional | - | 12 de Octubre de Itauguá | 1:1 | |
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| 12. Round | 16/10/2021 | Club Nacional | - | Sportivo Luqueño | 0:0 | |
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| 13. Round | 25/10/2021 | Libertad | - | Club Nacional | 1:2 | ||||
| 14. Round | 29/10/2021 | Club Nacional | - | River Plate | 1:1 | |
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| 15. Round | 08/11/2021 | Guaireña FC | - | Club Nacional | 0:0 | ||||
| 16. Round | 21/11/2021 | Club Nacional | - | Cerro Porteño | 1:5 | ||||
| 18. Round | 05/12/2021 | Club Nacional | - | Club Olimpia | 1:3 |
Paraguay