| 1. Round | 14/08/2021 | Everton FC | - | Southampton FC | 3:1 | ||||
| 2. Round | 22/08/2021 | Southampton FC | - | Manchester United | 1:1 |  |
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| 3. Round | 28/08/2021 | Newcastle United | - | Southampton FC | 2:2 | ||||
| 4. Round | 11/09/2021 | Southampton FC | - | West Ham United | 0:0 | |
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| 5. Round | 18/09/2021 | Manchester City | - | Southampton FC | 0:0 | ||||
| 16. Round | 11/12/2021 | Arsenal FC | - | Southampton FC | 3:0 | ||||
| 25. Round | 12/02/2022 | Manchester United | - | Southampton FC | 1:1 | ||||
| 27. Round | 25/02/2022 | Southampton FC | - | Norwich City | 2:0 | ||||
| 28. Round | 05/03/2022 | Aston Villa | - | Southampton FC | 4:0 | ||||
| 37. Round | 17/05/2022 | Southampton FC | - | Liverpool FC | 1:2 | |
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| 38. Round | 22/05/2022 | Leicester City | - | Southampton FC | 4:1 |
England
