| 2. Round | 16/01/2022 | Club Tijuana | - | Club León | 1:1 | ||||
| 3. Round | 23/01/2022 | Club León | - | CF Pachuca | 2:1 |  |
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| 4. Round | 08/02/2022 | Club León | - | Cruz Azul | 0:1 | ||||
| 5. Round | 13/02/2022 | Pumas UNAM | - | Club León | 2:1 | ||||
| 6. Round | 20/02/2022 | Club León | - | Deportivo Guadalajara | 2:1 | ||||
| 7. Round | 26/02/2022 | Club Necaxa | - | Club León | 0:1 | ||||
| 8. Round | 02/03/2022 | Club León | - | CF Monterrey | 0:0 | ||||
| 9. Round | 05/03/2022 | FC Juárez | - | Club León | 0:1 | ||||
| 10. Round | 12/03/2022 | Club León | - | UANL Tigres | 0:3 | ||||
| 11. Round | 21/03/2022 | Mazatlán FC | - | Club León | 1:2 | ||||
| 12. Round | 03/04/2022 | Club León | - | Gallos Blancos | 1:1 | ||||
| 13. Round | 09/04/2022 | Atlético San Luis | - | Club León | 2:0 | ||||
| 14. Round | 16/04/2022 | Club León | - | Puebla FC | 0:1 | ||||
| 15. Round | 21/04/2022 | CF América | - | Club León | 2:0 | ||||
| 16. Round | 25/04/2022 | Santos Laguna | - | Club León | 1:1 | ||||
| 17. Round | 02/05/2022 | Club León | - | Deportivo Toluca | 4:4 |
Colombia