| 2021-08-14 20:00:00za 14 aug 2021 |   Fortuna Sittard - FC Twente | 20:00:0020:00 | 2 - 1 | Fortuna Sittard Stadion |
| 2021-08-22 12:15:00zo 22 aug 2021 |  FC Twente - Ajax | 12:15:0012:15 | 1 - 1 | De Grolsch Veste |
| 2021-08-28 18:45:00za 28 aug 2021 |  SC Cambuur - FC Twente | 18:45:0018:45 | 2 - 0 | Cambuur Stadion |
| 2021-09-11 16:30:00za 11 sep 2021 |  FC Twente - FC Utrecht | 16:30:0016:30 | 1 - 0 | De Grolsch Veste |
| 2021-09-19 14:30:00zo 19 sep 2021 |  Vitesse - FC Twente | 14:30:0014:30 | 1 - 4 | GelreDome |
| 2021-09-23 21:00:00do 23 sep 2021 |  FC Twente - AZ Alkmaar | 21:00:0021:00 | 3 - 1 | De Grolsch Veste |
| 2021-09-26 14:30:00zo 26 sep 2021 |  SC Heerenveen - FC Twente | 14:30:0014:30 | 2 - 3 | Abe Lenstra Stadion |
| 2021-10-01 20:00:00vr 1 okt 2021 |  FC Groningen - FC Twente | 20:00:0020:00 | 1 - 1 | Hitachi Capital Mobility Stadion |
| 2021-10-17 16:45:00zo 17 okt 2021 |  FC Twente - Willem II | 16:45:0016:45 | 1 - 1 | De Grolsch Veste |
| 2021-10-24 12:15:00zo 24 okt 2021 |  FC Twente - N.E.C. Nijmegen | 12:15:0012:15 | 1 - 2 | De Grolsch Veste |
| 2021-10-30 16:30:00za 30 okt 2021 |  PSV - FC Twente | 16:30:0016:30 | 5 - 2 | Philips Stadion |
| 2021-11-05 20:00:00vr 5 nov 2021 |  FC Twente - Heracles | 20:00:0020:00 | 1 - 0 | De Grolsch Veste |
| 2021-11-20 18:45:00za 20 nov 2021 |  Sparta R’dam - FC Twente | 18:45:0018:45 | 0 - 1 | Het Kasteel |
| 2021-11-28 14:30:00zo 28 nov 2021 |  FC Twente - Feyenoord | 14:30:0014:30 | 0 - 0 | De Grolsch Veste |
| 2021-12-05 14:30:00zo 5 dec 2021 |  Go Ahead Eagles - FC Twente | 14:30:0014:30 | 1 - 2 | De Adelaarshorst |
| 2021-12-12 12:15:00zo 12 dec 2021 |  FC Twente - RKC Waalkwijk | 12:15:0012:15 | 2 - 1 | De Grolsch Veste |
| 2021-12-18 21:00:00za 18 dec 2021 |  PEC Zwolle - FC Twente | 21:00:0021:00 | 1 - 3 | MAC3PARK Stadion |
| 2021-12-22 21:00:00wo 22 dec 2021 | FC Utrecht - FC Twente | 21:00:0021:00 | 1 - 1 | De Galgenwaard |
| 2022-01-15 20:00:00za 15 jan 2022 | FC Twente - SC Heerenveen | 20:00:0020:00 | 2 - 0 | De Grolsch Veste |
| 2022-01-22 21:00:00za 22 jan 2022 | Willem II - FC Twente | 21:00:0021:00 | 0 - 1 | Koning Willem II Stadion |
| 2022-02-05 21:00:00za 5 feb 2022 | FC Twente - Vitesse | 21:00:0021:00 | 3 - 0 | De Grolsch Veste |
| 2022-02-13 16:45:00zo 13 feb 2022 | Ajax - FC Twente | 16:45:0016:45 | 5 - 0 | Johan Cruijff ArenA |
| 2022-02-20 14:30:00zo 20 feb 2022 | FC Twente - Go Ahead Eagles | 14:30:0014:30 | 2 - 2 | De Grolsch Veste |
| 2022-02-25 20:00:00vr 25 feb 2022 | RKC Waalkwijk - FC Twente | 20:00:0020:00 | 1 - 2 | Mandemakers Stadion |
| 2022-03-06 14:30:03zo 6 mrt 2022 | FC Twente - SC Cambuur | 14:30:0314:30 | 1 - 0 | De Grolsch Veste |
| 2022-03-13 20:00:07zo 13 mrt 2022 | AZ Alkmaar - FC Twente | 20:00:0720:00 | 0 - 1 | AFAS Stadion |
| 2022-03-19 20:00:04za 19 mrt 2022 | FC Twente - PEC Zwolle | 20:00:0420:00 | 1 - 0 | De Grolsch Veste |
| 2022-04-02 18:45:00za 2 apr 2022 | FC Twente - PSV | 18:45:0018:45 | 3 - 3 | De Grolsch Veste |
| 2022-04-09 21:00:00za 9 apr 2022 | N.E.C. Nijmegen - FC Twente | 21:00:0021:00 | 0 - 2 | Goffertstadion |
| 2022-04-22 20:00:00vr 22 apr 2022 | FC Twente - Sparta R'dam | 20:00:0020:00 | 2 - 0 | De Grolsch Veste |
| 2022-04-30 20:00:00za 30 apr 2022 | Heracles - FC Twente | 20:00:0020:00 | 1 - 1 | Erve Asito |
| 2022-05-07 18:45:00za 7 mei 2022 | FC Twente - Fortuna Sittard | 18:45:0018:45 | 1 - 2 | De Grolsch Veste |
| 2022-05-11 20:00:00wo 11 mei 2022 | FC Twente - FC Groningen | 20:00:0020:00 | 3 - 0 | De Grolsch Veste |
| 2022-05-15 14:30:00zo 15 mei 2022 | Feyenoord - FC Twente | 14:30:0014:30 | 1 - 2 | De Kuip |
