| 4. Round | 12/09/2021 | NEC Nijmegen | - | Willem II | 0:0 | ||||
| 5. Round | 18/09/2021 | Willem II | - | FC Groningen | 2:1 | ||||
| 7. Round | 25/09/2021 | Willem II | - | PSV Eindhoven | 2:1 | ||||
| 8. Round | 02/10/2021 | Heracles Almelo | - | Willem II | 3:2 | ||||
| 9. Round | 17/10/2021 | FC Twente | - | Willem II | 1:1 | ||||
| 11. Round | 31/10/2021 | FC Utrecht | - | Willem II | 5:1 | ||||
| 12. Round | 06/11/2021 | Willem II | - | Sparta Rotterdam | 0:3 | ||||
| 13. Round | 21/11/2021 | sc Heerenveen | - | Willem II | 2:1 | ||||
| 14. Round | 27/11/2021 | Willem II | - | Go Ahead Eagles | 0:1 | ||||
| 16. Round | 10/12/2021 | Willem II | - | SC Cambuur | 1:3 | ||||
| 18. Round | 22/12/2021 | Willem II | - | NEC Nijmegen | 0:1 | ||||
| 19. Round | 14/01/2022 | PEC Zwolle | - | Willem II | 2:0 | ||||
| 20. Round | 22/01/2022 | Willem II | - | FC Twente | 0:1 | ||||
| 21. Round | 06/02/2022 | Willem II | - | RKC Waalwijk | 3:1 | ||||
| 23. Round | 19/02/2022 | Willem II | - | AFC Ajax | 0:1 | ||||
| 24. Round | 26/02/2022 | FC Groningen | - | Willem II | 1:0 | ||||
| 29. Round | 08/04/2022 | Go Ahead Eagles | - | Willem II | 4:0 |
Greece