They beat Tottenham Hotspur 3-2 in the final at Old Trafford with second-half goals from Marnick Vermijl and a brace from Larnell Cole.
Warren Joyce's side were trailing 2-0 at half-time after goals from Jonathan Obika and Alex Pritchard.
"The two goals we conceded were due to poor individual errors really. Obviously the second half was better and our players' heart, character and fitness shone through in the end. I thought we thoroughly deserved to win," said Joyce after seeing Cole equalise in the 74th minute before netting the winner two minutes from time.
"The bulk of this side won the Youth Cup, won everything they could possibly win last season, they've won the Manchester Senior Cup this year and they've won that trophy tonight.
"They've shown a lot of character. They can take criticism, they can come back and dig themselves out of holes. That's what you're looking for in a Manchester United player."
There were 23 participating teams in the inaugural under-21 Premier League with United having beaten Liverpool 3-0 in the semi-finals and Spurs defeating Everton 3-2.