| 1. Round | 07/08/2021 | Salford City | - | Leyton Orient | 1:1 | ||||
| 2. Round | 14/08/2021 | Leyton Orient | - | Exeter City | 3:0 | ||||
| 4. Round | 21/08/2021 | Carlisle United | - | Leyton Orient | 1:1 | ||||
| 3. Round | 24/08/2021 | Leyton Orient | - | Harrogate Town | 0:2 | ||||
| 7. Round | 11/09/2021 | Leyton Orient | - | Oldham Athletic | 4:0 | ||||
| 8. Round | 18/09/2021 | Bristol Rovers | - | Leyton Orient | 1:3 | ||||
| 10. Round | 02/10/2021 | Port Vale FC | - | Leyton Orient | 3:2 | ||||
| 21. Round | 11/12/2021 | Leyton Orient | - | Crawley Town | 1:2 |  |
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| 22. Round | 18/12/2021 | Tranmere Rovers | - | Leyton Orient | 1:0 | |
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| 29. Round | 29/01/2022 | Mansfield Town | - | Leyton Orient | 2:0 | ||||
| 26. Round | 01/02/2022 | Bradford City | - | Leyton Orient | 1:1 | ||||
| 31. Round | 08/02/2022 | Exeter City | - | Leyton Orient | 1:0 |
England