| 1. Round | 23/07/2021 | Gallos Blancos | - | CF América | 0:0 |  |
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| 2. Round | 01/08/2021 | CF América | - | Club Necaxa | 2:1 | ||||
| 3. Round | 08/08/2021 | CF América | - | Puebla FC | 2:0 |  |
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| 4. Round | 15/08/2021 | Atlas Guadalajara | - | CF América | 0:1 | ||||
| 5. Round | 19/08/2021 | FC Juárez | - | CF América | 1:2 | |
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| 6. Round | 22/08/2021 | CF América | - | Club Tijuana | 2:0 | ||||
| 7. Round | 29/08/2021 | Club León | - | CF América | 1:1 | ||||
| 8. Round | 12/09/2021 | CF América | - | Mazatlán FC | 2:0 | ||||
| 9. Round | 19/09/2021 | Deportivo Toluca | - | CF América | 3:1 | ||||
| 10. Round | 26/09/2021 | CF América | - | Deportivo Guadalajara | 0:0 | ||||
| 11. Round | 29/09/2021 | CF Pachuca | - | CF América | 1:1 | ||||
| 12. Round | 03/10/2021 | CF América | - | Pumas UNAM | 2:0 | ||||
| 13. Round | 17/10/2021 | Atlético San Luis | - | CF América | 0:1 | |
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| 14. Round | 20/10/2021 | CF América | - | Santos Laguna | 2:1 | |
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| 17. Round | 07/11/2021 | CF América | - | CF Monterrey | 0:0 | |
Colombia