Three first-half goals in a Premier League match for the first time in their history had Albion in complete control at the midway stage of another disappointing afternoon for Jose Mourinho.
Romelu Lukaku converted from close range after Glenn Murray and Shane Duffy had put the hosts two goals ahead at the Amex Stadium, only for Pascal Gross to net from the penalty spot to leave his side on the brink of what would prove to be a straightforward win.
United did make the scoreline a tad more respectable in the final minute of the match thanks to Paul Pogba's penalty, but that came after they had mustered just one other shot on target in the second half when chasing a couple of goals.
Not since October 2015 had Man United shipped three goals in the first half of a league match, but that was the case on the south coast as they left themselves with a huge mountain to climb.
Prior to Murray's opener, Lukaku - back in the side as one of three United changes - scuffed a shot wide of the near post after giving goalkeeper Mathew Ryan the eyes.
Murray's impressive goal was added to two minutes later by Duffy, who was left in enough space to take two touches in front of goal after United failed to clear a corner, the second of which ended with the ball fizzing past De Gea.
United did pull one back through Lukaku's close-range header after Luke Shaw's miscued shot bounced nicely into his path, but Brighton restored their two-goal advantage before the break via a Gross penalty.
Gross stepped up and fired down the middle, getting the better of De Gea despite the Spaniard's foot touching the ball.
The change in personnel did not have the desired effect, as the visitors failed to get in a single shot of note prior to Marouane Fellaini's introduction on the hour.
Despite needing a couple of goals to rescue a point, Mourinho's side simply could not pick out the final pass in a second half devoid of any real action until the late penalty.
Not until the final 15 minutes did United finally step things up slightly, in fact, coming close through a well-hit Pogba shot that Ryan was equal to down low.
Duffy's challenge on Fellaini in the box five minutes into added time allowed Pogba to strike the ball down the middle from the penalty spot, but it came too late to spark a revival as United slipped to a third successive away league defeat in this fixture.
BRIGHTON & HOVE ALBION (4-4-1-1): Ryan; Montoya, Dunk (Balogun 20'), Duffy, Bong; March, Propper, Stephens, Knockaert; Gross (Kayal 90'); Murray (Locadia 93')
MANCHESTER UNITED (4-3-3): De Gea; Young, Lindelof, Bailly, Shaw; Pereira (Lingard 46'), Fred, Pogba; Martial (Fellaini 60'), Lukaku, Mata (Rashford 46')