First-half goals from Bruno Fernandes, with his second penalty in five days, a first United strike for Odion Ighalo and a comeback goal for Scott McTominay swept aside the Belgians.
Brugge had Simon Deli sent off for the handball that gave Bruno his spot-kick and the Reds took full advantage of the extra man.
Fred scored twice in the second half to complete the rout, his first goals of the season, as United strolled to a 6-1 aggregate win.
It was a hectic and entertaining start to the second leg with both United and Brugge posting early goal threats.