| 25.08.2021 | |||
| 21:00 | West Bromwich | 0-6 | Arsenal FC |
| 20:45 | Newcastle United | 0-0/p.3-4 | Burnley |
| 20:45 | Newport County | 0-8 | Southampton |
| 24.08.2021 | |||
| 21:00 | Nottingham Forest | 0-4 | Wolverhampton |
| 20:45 | Barrow AFC | 0-6 | Aston Villa |
| 20:45 | Birmingham City | 0-2 | Fulham |
| 20:45 | Blackpool | 2-3 | Sunderland |
| 20:45 | Brentford FC | 3-1 | Forest Green |
| 20:45 | Cardiff City | 0-2 | Brighton |
| 20:45 | Gillingham | 1-1/p.4-5 | Cheltenham |
| 20:45 | Huddersfield | 1-2 | Everton |
| 20:45 | Leeds United | 3-0 | Crewe Alexandra |
| 20:45 | Millwall FC | 3-1 | Cambridge United |
| 20:45 | Morecambe FC | 2-4 | Preston NE |
| 20:45 | Northampton | 0-1 | AFC Wimbledon |
| 20:45 | QPR | 2-0 | Oxford United |
| 20:45 | Sheffield United | 2-1 | Derby County |
| 20:45 | Shrewsbury | 0-2 | Rochdale |
| 20:45 | Stevenage FC | 2-2/p.3-5 | Wycombe |
| 20:45 | Stoke City | 2-0 | Doncaster Rovers |
| 20:45 | Watford FC | 1-0 | Crystal Palace |
| 20:45 | Wigan Athletic | 0-0/p.5-4 | Bolton Wanderers |
| 20:00 | Norwich City | 6-0 | Bournemouth |
| 20:00 | Oldham Athletic | 0-0/p.5-4 | Accrington Stanley |
| 20:00 | Swansea City | 4-1 | Plymouth Argyle |
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