| 4. Round | 22/07/2021 | Chicago Fire | - | D.C. United | 2:2 | ||||
| 5. Round | 05/08/2021 | Chicago Fire | - | New York City FC | 0:0 | ||||
| 5. Round | 15/08/2021 | Chicago Fire | - | Columbus Crew | 1:0 | ||||
| 5. Round | 19/08/2021 | Inter Miami CF | - | Chicago Fire | 3:2 | ||||
| 5. Round | 22/08/2021 | Orlando City | - | Chicago Fire | 1:0 | ||||
| 6. Round | 12/09/2021 | Sporting Kansas City | - | Chicago Fire | 2:0 | ||||
| 6. Round | 16/09/2021 | D.C. United | - | Chicago Fire | 3:0 | ||||
| 6. Round | 19/09/2021 | CF Montréal | - | Chicago Fire | 2:0 | ||||
| 7. Round | 03/10/2021 | Toronto FC | - | Chicago Fire | 3:1 | ||||
| 7. Round | 17/10/2021 | New England Revolution | - | Chicago Fire | 2:2 | ||||
| 8. Round | 07/11/2021 | Columbus Crew | - | Chicago Fire | 2:0 |  |
Bulgaria