| 1. Round | 26/07/2021 | CF Monterrey | - | Puebla FC | 1:1 |  |
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| 3. Round | 08/08/2021 | CF América | - | Puebla FC | 2:0 | ||||
| 4. Round | 14/08/2021 | Puebla FC | - | UANL Tigres | 1:1 | ||||
| 5. Round | 18/08/2021 | Club Tijuana | - | Puebla FC | 1:1 | ||||
| 6. Round | 22/08/2021 | Pumas UNAM | - | Puebla FC | 2:0 | ||||
| 7. Round | 28/08/2021 | Puebla FC | - | Gallos Blancos | 1:0 | ||||
| 8. Round | 11/09/2021 | Puebla FC | - | Atlético San Luis | 2:2 | ||||
| 9. Round | 20/09/2021 | Santos Laguna | - | Puebla FC | 1:1 | ||||
| 10. Round | 25/09/2021 | Puebla FC | - | Cruz Azul | 1:1 | ||||
| 11. Round | 29/09/2021 | Atlas Guadalajara | - | Puebla FC | 0:1 | |
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| 12. Round | 02/10/2021 | Puebla FC | - | CF Pachuca | 1:2 | |
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| 13. Round | 16/10/2021 | Club Necaxa | - | Puebla FC | 0:1 | ||||
| 14. Round | 20/10/2021 | Puebla FC | - | Mazatlán FC | 2:0 | |
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| 15. Round | 23/10/2021 | Puebla FC | - | Club León | 0:1 | |
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| 16. Round | 30/10/2021 | FC Juárez | - | Puebla FC | 0:2 | |
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| 17. Round | 06/11/2021 | Puebla FC | - | Deportivo Toluca | 1:0 | |
Uruguay
Spain