The 20-year-old midfielder won't play again this year after damaging his ACL in the opening day draw with Bolton.
Hughes was stretchered off roughly half an hour into the goalless draw at Bolton Wanderers on Saturday after seemingly getting his studs caught in the turf at the Macron Stadium, with Ryan Shotton coming on in his place.
The Rams website announced that the talented playmaker will undergo "immediate surgery", and will now have to wait until 2016 until he can play again, in what is a huge blow both to the youngster's development and Derby's hopes of promotion this season.
Hughes has been a mainstay of the Derby side since bursting into first team football at the end of the 2011-12 season, becoming a regular option in midfield in the three seasons since, including 48 appearances last season as Steve McClaren's side just missed out on the playoffs.
Hughes featured in the European Under-21 Championships this summer for England, and has won 17 caps or his country at that level.
As one of the Rams key players, manager Paul Clement may well feel that a replacement has to be brought in via the transfer market, whether it's on loan or a permanent signing, especially considering the severity of the knee injury.
ACL problems can end up taking significantly longer to rehabilitate from than projected after the initial injury recovery, and trying to bring Hughes back into the side headlining in to the frantic Spring period would be a risky strategy. Backup in central midfield would mean Derby were covered until his return, and ensure he could be gradually reintroduced to the team.