Hughes, 17, became the second youngest player after Theo Walcott to represent the Young Lions when he made his debut as a substitute against Northern Ireland in November, and he has kept his place in the squad for the game at Walsall's Banks's Stadium on February 5.
Rams boss Nigel Cough told his club's official website: "It's another great achievement for Will to actually retain his place in the England Under-21 set-up and we're delighted that he's received another call-up.
"Given he's been a regular in our team this season, people may well forget the fact that he is only 17 and to receive a call-up to the England Under-21 team at that age speaks volumes for Will's performances and potential.
"When he played for England Under-21s last time, it gave him a little lift and we are hoping another call-up will do the same.
"And once again it's great news for our academy and the club as a whole."
Hughes becomes the 10th Derby player to be recognised by his country ahead of next week's internationals.
Jeff Hendrick, Richard Keogh and Conor Sammon (Republic of Ireland), Jamie Ward (Northern Ireland), Theo Robinson (Jamaica), Mark O'Brien (Republic of Ireland Under-21s), Kieron Freeman (Wales Under-21s), Mason Bennett (England Under-17s) and Valentin Gjokaj (Albania Under-21s) have also been called up for international duty.