| 1. Round | 24/07/2021 | Club Necaxa | - | Santos Laguna | 0:3 |  |
|||
| 2. Round | 02/08/2021 | Santos Laguna | - | Cruz Azul | 1:1 | ||||
| 3. Round | 08/08/2021 | UANL Tigres | - | Santos Laguna | 1:1 | ||||
| 4. Round | 16/08/2021 | Santos Laguna | - | Deportivo Guadalajara | 0:0 | ||||
| 5. Round | 19/08/2021 | Santos Laguna | - | Atlas Guadalajara | 1:1 | ||||
| 6. Round | 22/08/2021 | Club León | - | Santos Laguna | 1:1 | ||||
| 7. Round | 30/08/2021 | Santos Laguna | - | FC Juárez | 2:0 | ||||
| 8. Round | 11/09/2021 | Club Tijuana | - | Santos Laguna | 2:1 |  |
|||
| 9. Round | 20/09/2021 | Santos Laguna | - | Puebla FC | 1:1 | ||||
| 10. Round | 27/09/2021 | Santos Laguna | - | CF Monterrey | 1:2 | ||||
| 12. Round | 03/10/2021 | Santos Laguna | - | Mazatlán FC | 1:0 | ||||
| 13. Round | 17/10/2021 | CF Pachuca | - | Santos Laguna | 1:1 | ||||
| 14. Round | 20/10/2021 | CF América | - | Santos Laguna | 2:1 | ||||
| 15. Round | 25/10/2021 | Santos Laguna | - | Deportivo Toluca | 2:2 | ||||
| 16. Round | 30/10/2021 | Gallos Blancos | - | Santos Laguna | 2:3 | ||||
| 11. Round | 05/11/2021 | Pumas UNAM | - | Santos Laguna | 0:3 | ||||
| 17. Round | 08/11/2021 | Santos Laguna | - | Atlético San Luis | 0:0 |
Colombia