The Blades had fought back from 2-0 down to level at 2-2 through goals from Gus Hamer and Will Osula before the break, before Joao Pedro sealed his hat-trick with two more goals in the second period.
Pedro scored twice from the penalty spot, both spot-kicks conceded by Jayden Bogle, before sub Danny Welbeck capped victory with a fifth deep into stoppage time which squirmed through the grasp of Blades debut goalkeeper Ivo Grbic.
United can now at least put full focus on their Premier League survival bid, with Crystal Palace next up for the Blades on Tuesday night. Here's how we rated Chris Wilder's side as they tumbled out of the FA Cup...
1. Ivo Grbic 4.5
He won't have dreamed about conceding five goals on his debut when his head hit the pillow last night but in truth there was little he could have done about the first four of them - two well-hit long-range efforts and two penalties. "Bring back Wes" shouted one fan on the South Stand, which seems a bit harsh on the new man on his first taste of English football, but he could have done better with Brighton's fifth late on as Welbeck's shot squeezed through him
2. Jayden Bogle 4
One of the Blades' leading lights since Wilder's return but couldn't match his own high standards here on a tough afternoon which saw him give away two penalties. Took a gamble with his challenge on Pedro and it didn't pay off as the referee - eventually - pointed to the spot. He then conceded another in the second half for handball as he jumped with Ferguson but almost began his redemption with a goal, before his shot was deflected inches wide
3. Anel Ahmedhodzic 5
Turned too easily by Pedro on his way to winning Brighton's first penalty and then couldn't get out quickly enough to close down the Albion No.9 as he turned and smashed home for his hat-trick, although he might argue that one of his defenders should have dropped deep to do the job instead. An unconvincing display for United's backline
4. Auston Trusty 5
Not his usual composed self early on as he hacked a cross behind but in fairness owned the error to his teammates. Did better in the second half to cut out a dangerous cross that Ferguson otherwise would have tapped in. Could and probably should have done better with a late header from Norwood's corner that he couldn't get on target