| 1. Round | 18/07/2021 | Guaraní | - | Sol de América | 3:0 | ||||
| 2. Round | 24/07/2021 | Club Nacional | - | Guaraní | 1:1 |  |
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| 3. Round | 01/08/2021 | Guaraní | - | 12 de Octubre de Itauguá | 4:1 | ||||
| 4. Round | 07/08/2021 | Guaraní | - | Club Olimpia | 3:1 | ||||
| 6. Round | 24/08/2021 | Guaraní | - | Libertad | 2:2 |  |
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| 7. Round | 30/08/2021 | River Plate | - | Guaraní | 1:5 | ||||
| 8. Round | 12/09/2021 | Guaraní | - | Guaireña FC | 3:0 | |
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| 9. Round | 19/09/2021 | Cerro Porteño | - | Guaraní | 0:0 | |
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| 10. Round | 28/09/2021 | Sol de América | - | Guaraní | 2:1 | ||||
| 11. Round | 03/10/2021 | Guaraní | - | Club Nacional | 1:1 | |
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| 12. Round | 18/10/2021 | 12 de Octubre de Itauguá | - | Guaraní | 1:2 | ||||
| 13. Round | 24/10/2021 | Club Olimpia | - | Guaraní | 1:3 | ||||
| 14. Round | 31/10/2021 | Guaraní | - | Sportivo Luqueño | 2:1 | ||||
| 15. Round | 07/11/2021 | Libertad | - | Guaraní | 2:0 | ||||
| 16. Round | 20/11/2021 | Guaraní | - | River Plate | 2:1 | ||||
| 17. Round | 28/11/2021 | Guaireña FC | - | Guaraní | 1:1 | ||||
| 18. Round | 04/12/2021 | Guaraní | - | Cerro Porteño | 2:2 | |
Uruguay