Moises Caicedo struck a fine first-half effort beyond David de Gea, but worse was to come for United after half-time as Brighton took advantage of a dismal performance from the visitors.
Marc Cucurella, Pascal Gross and Leandro Trossard each scored in quick succession, with the Belgium winger finishing with a goal and two assists.
The result marked a new low in the Red Devils' woeful season, with their tally of 56 Premier League goals conceded this term representing the most in a single campaign in the competition's history.
Ralf Rangnick opted not to restore fit-again captain Harry Maguire to his defence, which was breached after 15 minutes when Caicedo drilled a brilliant finish into the bottom-left corner from outside the area.
Victor Lindelof was forced into a last-ditch clearance after a flowing move from the dominant hosts, before Danny Welbeck lobbed over the bar after latching on to Raphael Varane's poor touch.
Rangnick introduced Fred and Edinson Cavani after watching his team fail to register a shot on target before the break, but Cucurella then side-footed home from Trossard's 49th-minute cutback.
Brighton ended the game as a contest after 57 minutes when Gross produced a neat left-footed finish after taking Trossard's pass into his stride, and it was in dreamland as the creator turned scorer three minutes later, bundling in from close range after Welbeck's chipped effort.
Brighton almost had a fifth after 65 minutes when Diogo Dalot deflected Alexis Mac Allister's effort against his own post, while Welbeck also narrowly missed the target again as United endured another day to forget – Cavani's consolation ruled out for offside at the other end.
United's capitulation saw the positivity of Tuesday's (AEST) 3-0 win over Brentford evaporate and confirmed the 2021-2022 season will be its worst in the Premier League.
With 58 points and just one game remaining, United will finish with its lowest points tally in the competition, unable to match the 64 it earned in 2013-2014 under David Moyes and Ryan Giggs.
United has now conceded four or more goals in 12 separate Premier League matches since Alex Ferguson's 2013 retirement, as many as it did in 810 games under him in the competition.
After defeats at Manchester City, Everton, Liverpool and Arsenal with another on the road, this is United's worst such run since it lost six away league games in a row between December 1980 and March 1981.
It could yet match that sequence when it goes to Crystal Palace on the Premier League's final day.