Juan Mata, Marcos Rojo and second-half substitute James Wilson scored in the 3-0 win which sent United through to a fifth-round tie at League One Preston.
Cambridge failed to match the heroics of Bradford and Middlesbrough - who knocked out Chelsea and Manchester City respectively - but it could have been a much different story had Tom Elliott converted a great opportunity after just 50 seconds.
Cambridge will not care about that though
The 6,500 fans they brought to Old Trafford - and the supporters they have won along this FA Cup run - were just delighted the team made it this far.
And in fairness to the League Two outfit they put up more than a fight in their two fixtures against the 20-time English champions.
The 0-0 draw against United 11 days ago will live long in the memory of the club's fans - as will their trip to Old Trafford, where they came up against a team worth almost £240million.
The £1million windfall the minnows have earned from this replay will come in particularly handy to Cambridge, who have an annual turnover of £1.6million.
Manager Louis van Gaal had complained "everything was against" Manchester United in the original fixture, but he knew he had no excuses this time around.
Van Gaal told home fans not to expect a walkover in his programme notes, but his players did not heed his warning and the visitors nearly took a shock lead just after kick-off.
With less than a minute gone, Daley Blind slipped and somehow sent Elliott through on goal.
The big striker, clearly taken aback by the opportunity at his feet, just about managed to maintain his balance and bent a shot past David de Gea with the instep of his right boot.
Luckily for the hosts there was not enough curl on the shot, which hit the outside of the post and bounced to safety.
The 20-time league champions regained their composure, but the 4-1-4-1 formation Van Gaal played seemed to hinder their ability to carve open the away defence.
Wayne Rooney was marooned out on the right side and Marouane Fellaini was playing right up front on Robin van Persie's shoulder.
Rooney had Manchester United's first shot on target - a weak effort that nestled into Chris Dunn's arms
And the Red Devils captain was denied again by a crunching tackle from Cameron McGeehan.
Nothing was really going for Manchester United and their fans became impatient.
Angel di Maria, shortly after receiving treatment for a foul by McGeehan, tried to slide Mata through but the £60million man's pass was too heavy.
The Cambridge fans were revelling in the fact that they were holding a team sat 79 places above them in the league pyramid.
But their defence was finally breached in the 25th minute
Di Maria latched on to a clever pass from Paddy McNair and whipped a cross to the back post
Fellaini nodded the ball down to Mata and he stabbed the ball in off the bar.
Seven minutes later the nerves inside Old Trafford eased further as the lead was doubled.
Fellaini's shot was deflected into the path of Van Persie, who curled a short-range cross with the outside of his left boot to find Rojo, who headed in his first goal for the club.
Former Manchester United midfielder Luke Chadwick received a standing ovation from both sets of fans when he was replaced just after the break.
As the second half progressed, Cambridge began to tire
De Gea saved Robbie Simpson's header, but Cambridge rarely crossed the halfway line.
The home side were firmly on top and it only looked a matter of time before they added their third.
Rooney went close when he fired a fierce volley at Dunn and Van Persie snatched at the follow-up.
Van Persie chested the ball down and unleashed a volley on goal, but Dunn saved
The Cambridge goalkeeper then pulled off an acrobatic save to deny Di Maria from long range.
Di Maria and Van Persie both came off and their two replacements combined for the third goal when it arrived in the 73rd minute.
Ander Herrera drove at the Cambridge defence and laid the ball off for Wilson, who smacked a powerful low shot across Dunn into the far corner.
McGeehan had a chance to snatch a goal back for Cambridge in added time, but his shot flew just wide of De Gea's goal.
Source : PA
Source: PA