| 1. Round | 11/01/2021 | Santos Laguna | - | Cruz Azul | 1:0 | ||||
| 2. Round | 18/01/2021 | Santos Laguna | - | UANL Tigres | 2:0 |  |
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| 3. Round | 23/01/2021 | Mazatlán FC | - | Santos Laguna | 0:0 | ||||
| 4. Round | 01/02/2021 | Santos Laguna | - | CF América | 1:1 | ||||
| 5. Round | 06/02/2021 | Atlas Guadalajara | - | Santos Laguna | 1:1 | ||||
| 6. Round | 15/02/2021 | Santos Laguna | - | CF Monterrey | 1:0 |  |
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| 7. Round | 19/02/2021 | Atlético San Luis | - | Santos Laguna | 1:0 | |
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| 8. Round | 01/03/2021 | Santos Laguna | - | FC Juárez | 3:2 | ||||
| 9. Round | 05/03/2021 | Pumas UNAM | - | Santos Laguna | 1:0 | |
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| 10. Round | 08/03/2021 | Santos Laguna | - | Club Necaxa | 3:1 | |
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| 11. Round | 14/03/2021 | Club Tijuana | - | Santos Laguna | 0:1 | ||||
| 12. Round | 22/03/2021 | Santos Laguna | - | Club León | 1:2 | ||||
| 13. Round | 04/04/2021 | Deportivo Guadalajara | - | Santos Laguna | 1:1 | |
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| 14. Round | 12/04/2021 | Gallos Blancos | - | Santos Laguna | 1:0 | ||||
| 15. Round | 19/04/2021 | Santos Laguna | - | Deportivo Toluca | 3:1 | |
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| 16. Round | 27/04/2021 | CF Pachuca | - | Santos Laguna | 1:0 | ||||
| 17. Round | 03/05/2021 | Santos Laguna | - | Puebla FC | 0:0 |
Colombia