Kevin Schade could have scored twice for Brentford in the opening few minutes, first directing a cross just wide with Altay Bayındır wildly out of position before sliding in at the back post only to see the ball miss the post.
However, United then took the lead with what was their only shot of the first half, as Alejandro Garnacho picked out Mason Mount, who tapped home just his second goal for the club - his first incidentally also came against Brentford.
The Bees managed to turn the game around before HT though, as Mikkel Damsgaard’s strike deflected in off the unfortunate Luke Shaw after Michael Kayode’s long throw caused chaos.
Schade then got the goal he was threatening as he headed in Christian Nørgaard’s back-post cross. Brentford could have gone further ahead too, as Bayındır parried Schade’s effort away before brilliantly meeting Nørgaard’s header from close range.
To their credit, United started the second half better, with Mount having two shots at goal that admittedly didn’t threaten.
Kayode’s long throws were still causing problems for the Red Devils though, and one of them was flicked on dangerously before Yoane Wissa poked just wide at the back post.
Brentford’s mounting pressure told when Schade headed in his second of the match, connecting with Bryan Mbeumo’s whipped cross and to their delight, a quickfire fourth then came soon after via Wissa’s tap-in.
United managed to make things nervy late on, as Garnacho brilliantly curled into the top corner from outside the box, before substitute Amad Diallo’s shot went through Mark Flekken’s legs.
Nevertheless, the Bees extended their unbeaten league run to five matches as they won for just the second time in 13 H2Hs against United, while the visitors have now won just three of their last 22 trips to London.
Flashscore Man of the Match: Kevin Schade (Brentford)