| 2. Round | 13/02/2022 | Club Nacional | - | Cerro Porteño | 2:3 |  |
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| 3. Round | 18/02/2022 | Resistencia SC | - | Club Nacional | 3:1 | ||||
| 4. Round | 25/02/2022 | Club Nacional | - | 12 de Octubre de Itauguá | 2:2 | ||||
| 5. Round | 04/03/2022 | General Caballero DJLM | - | Club Nacional | 1:2 | ||||
| 6. Round | 14/03/2022 | Club Nacional | - | Libertad | 0:3 | ||||
| 8. Round | 03/04/2022 | Club Nacional | - | Sportivo Ameliano | 2:1 | |
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| 9. Round | 09/04/2022 | Club Olimpia | - | Club Nacional | 1:2 | ||||
| 10. Round | 17/04/2022 | Guaraní | - | Club Nacional | 0:1 | |
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| 11. Round | 20/04/2022 | Club Nacional | - | Guaireña FC | 3:1 | ||||
| 12. Round | 26/04/2022 | Club Nacional | - | Sol de América | 0:3 | ||||
| 13. Round | 01/05/2022 | Cerro Porteño | - | Club Nacional | 1:0 |  |
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| 15. Round | 10/05/2022 | 12 de Octubre de Itauguá | - | Club Nacional | 1:2 | ||||
| 16. Round | 14/05/2022 | Club Nacional | - | General Caballero DJLM | 1:2 | ||||
| 17. Round | 23/05/2022 | Libertad | - | Club Nacional | 1:0 | |
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| 20. Round | 23/06/2022 | Club Nacional | - | Club Olimpia | 1:1 | ||||
| 21. Round | 26/06/2022 | Club Nacional | - | Guaraní | 0:1 | ||||
| 22. Round | 01/07/2022 | Guaireña FC | - | Club Nacional | 1:1 |
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