Lukaku headed in a first-half cross from Nemanja Matic, who sealed victory late on when he nodded in Ashley Young's free-kick.
Victory maintained realistic United hopes of a trophy after Tuesday's Champions League elimination by Sevilla, as well as their record of not having conceded a goal in this season's FA Cup.
But Jose Mourinho's side struggled through the second half, as Brighton had several chances to force extra-time before Matic finally put the tie to bed.
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Home fans, angry about the unadventurous performance in defeat by Sevilla, became increasingly tetchy as the game wore on.
Jurgen Locadia, Brighton's £14m record signing, had four chances to equalise, with goalkeeper Sergio Romero saving the first two before the Dutchman headed over wastefully from Solly March's cross.
He then had a shot blocked by Chris Smalling, who had hit the post for United before Lukaku's goal.
Mourinho's 'heritage' players see him through
Romelu Lukaku's goal was his 25th in 44 appearances for Manchester United
"One day, when I leave, the next Manchester United manager will find here Lukaku, Matic, of course De Gea from many years ago. They will find players with a different mentality, quality, background, with a different status, knowhow."
In the midst of an extraordinary 12-minute defence of his United record on Friday, in which he referred repeatedly to "football heritage", Mourinho mentioned two outfield signings as evidence that he has improved the team since his arrival in May 2016.
He might, then, have felt some satisfaction that Lukaku and Matic were the players whose goals took United to April's Wembley semi-finals. In truth, there was little else for him to be pleased about.
Lukaku's opener - maintaining his record of having scored in every round of this season's FA Cup - came at a good time for United; Brighton had just enjoyed a sustained spell of possession.
He got in behind Lewis Dunk to score from a terrific Matic cross for his 25th club goal of the season - although there was a key role played too by Luke Shaw, a Louis van Gaal signing. The left-back ran at Solly March, pinning back the winger, before laying back into space for Matic to play the ball in.
Yet Shaw's role in the goal was not enough to keep him on the pitch beyond half-time. Mourinho, who has been critical repeatedly of the left-back, decided to bring on Young for the second half.
Young provided the assist for the second goal, headed in by Matic, from what was United's only effort on goal in the second half.
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