| 1. Round | 17/07/2021 | 12 de Octubre de Itauguá | - | Club Nacional | 2:2 |  |
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| 2. Round | 24/07/2021 | Club Nacional | - | Guaraní | 1:1 | ||||
| 3. Round | 31/07/2021 | Sportivo Luqueño | - | Club Nacional | 2:1 | ||||
| 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 |  |
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| 7. Round | 29/08/2021 | Cerro Porteño | - | Club Nacional | 0:2 | ||||
| 8. Round | 11/09/2021 | Club Nacional | - | Sol de América | 1:1 | ||||
| 9. Round | 21/09/2021 | Club Olimpia | - | Club Nacional | 1:2 | |
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| 10. Round | 25/09/2021 | Club Nacional | - | 12 de Octubre de Itauguá | 1:1 | ||||
| 11. Round | 03/10/2021 | Guaraní | - | Club Nacional | 1:1 | ||||
| 12. Round | 16/10/2021 | Club Nacional | - | Sportivo Luqueño | 0:0 | ||||
| 13. Round | 25/10/2021 | Libertad | - | Club Nacional | 1:2 | ||||
| 14. Round | 29/10/2021 | Club Nacional | - | River Plate | 1:1 | ||||
| 15. Round | 08/11/2021 | Guaireña FC | - | Club Nacional | 0:0 | ||||
| 16. Round | 21/11/2021 | Club Nacional | - | Cerro Porteño | 1:5 | ||||
| 17. Round | 26/11/2021 | Sol de América | - | Club Nacional | 3:0 | ||||
| 18. Round | 05/12/2021 | Club Nacional | - | Club Olimpia | 1:3 |
Argentina