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| 21/09/2021 | 19:45 | Queens Park Rangers | - | Everton FC | 8:7 (2:1, 2:2) pso | |
| 19:45 | Preston North End | - | Cheltenham Town | 4:1 (2:0) | ||
| 19:45 | Fulham FC | - | Leeds United | 5:6 (0:0, 0:0) pso | ||
| 19:45 | Brentford FC | - | Oldham Athletic | 7:0 (5:0) | ||
| 19:45 | Watford FC | - | Stoke City | 1:3 (0:1) | ||
| 19:45 | Wigan Athletic | - | Sunderland AFC | 0:2 (0:1) | ||
| 19:45 | Norwich City | - | Liverpool FC | 0:3 (0:1) | ||
| 19:45 | Burnley FC | - | Rochdale AFC | 4:1 (0:0) | ||
| 19:45 | Sheffield United | - | Southampton FC | 2:4 (1:1, 2:2) pso | ||
| 19:45 | Manchester City | - | Wycombe Wanderers | 6:1 (3:1) | ||
| 22/09/2021 | 19:30 | Brighton & Hove Albion | - | Swansea City | 2:0 (2:0) | |
| 19:45 | Manchester United | - | West Ham United | 0:1 (0:1) | ||
| 19:45 | Chelsea FC | - | Aston Villa | 4:3 (0:0, 1:1) pso | ||
| 19:45 | Arsenal FC | - | AFC Wimbledon | 3:0 (1:0) | ||
| 19:45 | Millwall FC | - | Leicester City | 0:2 (0:0) | ||
| 19:45 | Wolverhampton Wanderers | - | Tottenham Hotspur | 2:3 (1:2, 2:2) pso |
