In a game which lacked almost all of the drama from the Premier League meeting at the Amex Stadium four days earlier, the visitors advanced with a deserved 3-0 victory.
Juan Mata laid on the opener for Scott McTominay before adding the second himself with his 50th goal for the club.
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Paul Pogba came off the bench to score late on as Ole Gunnar Solskjaer’s side eased into the last eight.
Brighton made nine changes and United 10 from their weekend clash which was won by Bruno Fernandes’ penalty awarded after the full-time whistle.
On a rain-soaked evening this was no match for that five-goal thriller as United won their third game at Brighton in three months.
Like last week’s third-round win at Luton, Solskjaer handed a start to summer signing Donny Van De Beek while the likes of Mata, Dan James and Eric Bailly were also recalled.
There was also a rare start for Diogo Dalot, who has been linked with a move away from Old Trafford before the transfer window closes on Monday.
Graham Potter retained Ben White and captain Lewis Dunk as the Seagulls failed to gain retribution for their painful weekend defeat.
United laboured at times on Saturday but here there was at least the odd glimpse of the swashbuckling display which saw them brush Brighton aside in the Premier League back in June.
There was little for either goalkeeper to do in the opening exchanges, Odion Ighalo hitting the side-netting for United before the hosts drew a save out of Dean Henderson courtesy of Alireza Jahanbakhsh’s effort.
United took the lead just before the interval, Mata picking himself up after being tripped by Dan Burn to bend in a free-kick which McTominay headed home.
The second half followed a similar pattern with neither side able to create a string of chances.
Leandro Trossard hit the woodwork three times on Saturday and was denied again here by a fine Henderson stop.
Dunk then headed over when he arguably should have done better, but Brighton were not able to stage a rousing cup comeback.
Those chances were enough for Solskjaer to call for the cavalry as Pogba and Marcus Rashford were introduced from the bench with a little under 30 minutes remaining.
The tie was wrapped up shortly after as Mata finished with aplomb having been teed up by Van De Beek.
There was still time for Pogba to score just his second goal of 2020, the France midfielder seeing a free-kick take a big deflection on its way past Jason Steele.
