Hughes, at 17 years and 220 days, was named as one of nine substitutes and his big moment arrived after 66 minutes when he replaced Josh McEachran, the Chelsea midfielder who is on loan at the Rams' Championship rivals Middlesbrough.
Only Arsenal's Theo Walcott, who made his England Under-21 debut aged 17 years and 152 days, has been younger than Hughes.
Derby boss Nigel Clough told the club's official website: "We're all very proud of Will.
"It's a great achievement for someone of his age to be in the Under-21 squad and everyone connected with Derby County is exceptionally proud of Will."
England won the game at Blackpool's Bloomfield Road 2-0 thanks to goals from Sunderland striker Conor Wickham and Bolton's on-loan Arsenal striker Benik Afobe.