| 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 |  |
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| 8. Round | 03/03/2022 | Santos Laguna | - | Pumas UNAM | 3:2 | |
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| 9. Round | 06/03/2022 | Deportivo Guadalajara | - | Santos Laguna | 1:0 | ||||
| 10. Round | 14/03/2022 | Santos Laguna | - | Club Tijuana | 4:0 | |
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| 11. Round | 19/03/2022 | Puebla FC | - | Santos Laguna | 2:2 | |
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| 12. Round | 04/04/2022 | Santos Laguna | - | CF Pachuca | 3:1 | |
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| 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 | |
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| 16. Round | 25/04/2022 | Santos Laguna | - | Club León | 1:1 | ||||
| 17. Round | 01/05/2022 | Atlético San Luis | - | Santos Laguna | 1:3 |
Colombia