| 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 | ||||
| 14. Round | 20/10/2021 | CF América | - | Santos Laguna | 2:1 | ||||
| 16. Round | 30/10/2021 | Gallos Blancos | - | Santos Laguna | 2:3 | ||||
| 17. Round | 08/11/2021 | Santos Laguna | - | Atlético San Luis | 0:0 |
Mexico