| 1. Round | 13/01/2022 | Santos Laguna | - | UANL Tigres | 1:1 | ||||
| 2. Round | 16/01/2022 | Deportivo Toluca | - | Santos Laguna | 3:1 | ||||
| 3. Round | 24/01/2022 | Santos Laguna | - | Club Necaxa | 1:4 |  |
|||
| 4. Round | 07/02/2022 | Atlas Guadalajara | - | Santos Laguna | 2:1 | ||||
| 5. Round | 13/02/2022 | Santos Laguna | - | CF América | 2:3 | ||||
| 6. Round | 19/02/2022 | FC Juárez | - | Santos Laguna | 0:0 |  |
|||
| 7. Round | 28/02/2022 | Cruz Azul | - | Santos Laguna | 1:2 | ||||
| 8. Round | 03/03/2022 | Santos Laguna | - | Pumas UNAM | 3:2 | ||||
| 9. Round | 06/03/2022 | Deportivo Guadalajara | - | Santos Laguna | 1:0 | |
|||
| 10. Round | 14/03/2022 | Santos Laguna | - | Club Tijuana | 4:0 | ||||
| 11. Round | 19/03/2022 | Puebla FC | - | Santos Laguna | 2:2 | ||||
| 12. Round | 04/04/2022 | Santos Laguna | - | CF Pachuca | 3:1 | ||||
| 13. Round | 10/04/2022 | CF Monterrey | - | Santos Laguna | 1:0 | ||||
| 14. Round | 17/04/2022 | Santos Laguna | - | Gallos Blancos | 1:1 | ||||
| 15. Round | 20/04/2022 | Mazatlán FC | - | Santos Laguna | 1:0 |  |
|||
| 17. Round | 01/05/2022 | Atlético San Luis | - | Santos Laguna | 1:3 | |
Ecuador