Goals from Marouane Fellaini, Chris Smalling, Henrikh Mkhitaryan and Bastian Schweinsteiger sealed the victory for the Red Devils.
Championship outfit Fulham went toe-to-toe with Premier League club Hull City and emerged deserved 4-1 winners at Craven Cottage.
Fulham got off to a good start to the match, with Sone Aluko giving them the lead just 17 minutes into the match. Hull responded well and were level four minutes after half time with Evandro hitting the back of the net.
However, a pumped up Cottagers outfit were not to be denied with Chris Martin restoring their advantage in the 54th minute before 16-year-old Ryan Sessegnon all but secured their passage into the fifth round when he made it 3-1 in the 66th minute.
And they were not done there, as Stefan Johansen added a fourth in the 78th minute to complete an emphatic victory for the homes side.
Steve Morrison scored five minutes from time as League One side Millwall caused a major upset by dumping Watford out.
Millwall should have taken the lead inside the first minute but Steve Morrison headed against the woodwork as the hosts made a fast start.
The hosts continued to apply pressure and were rewarded when Morrison handed them the victory five minutes from time, slotting home Shane Ferguson's cross.
Non-League Sutton caused a major surprise when they defeated Championship side Leeds United 1-0 thanks to a penalty from Jamie Collins early in the second half.