Sir Alex Ferguson changed his entire XI from Sunday's 6-1 hammering at the hands of local rivals City - Tom Cleverley was a notable inclusion as he returned from injury - and his second-string side duly did the business as United booked their place in the quarter-finals.
Dimitar Berbatov got the ball rolling on 15 minutes, finishing in the corner after a slick passing move.
Michael Owen doubled the lead in fortunate circumstances, his effort squirming through Shots keeper Ross Worner.
Antonio Valencia put the seal on the win with a 25-yard strike shortly after the break.
Arsenal joined United in the last eight coutesy of a 2-1 win over Bolton at the Emirates.
They did it the hard way though, coming from a goal down.
Both sides made large numbers of changes - including Thomas Vermaelen returning for Arsenal after a lengthy injury spell - and it showed in a goalless first half.
A shock looked on the cards when Wanderers opened ther scoring on 47 minutes.
Fabrice Muamba played a neat one-two with Martin Petrov before rifling into the roof of the net.
However, the impressive Andrey Arshavin took just six minutes to respond, firing home low after Bolton's defenders backed off.
Korean striker Park Chu-young then put the Gunners in front with a curling effort - his first goal for the club following his summer move from Monaco.
Championship leaders Southampton bowed out of the competition, losing 2-0 at Crystal Palace.
Goals in the last 17 minutes by Darren Ambrose and Jermaine Easter (penalty) saw the home fans go home happy from Selhurst Park.
In the night's other tie, another all-Championship tussle, Cardiff saw off Burnley 1-0.
Joe Mason's 40th-minute shot ended up separating the sides in south Wales.
The other four last-16 ties take place on Wednesday with the quarter-final draw set for Saturday.