United went to the lockers room with a two-goal lead thanks to strikes from Wayne Rooney and Louis Saha.
Tunisian full-back Hatem Trabelsi pulled one back in the second-half but Cristiano Ronaldo ensured United's win six minutes from time.
The Red Devils are in charge of the league table with 44 points, nine ahead of second-placed Chelsea, who face London rivals Arsenal at the Stamford Bridge on Sunday.
Rooney put United ahead as early as the sixth minute when he connected with Ronaldo's cross from the right flank to slot home past City keeper Nicky Weaver.
Saha doubled the lead just before the break after Gabriel Heinze capitalized on Richard Dunne's failure to clear the ball and provided a cross to the French international, who made no mistake from close range.
Trabelsi scored his first goal for City to revive their hopes after firing a powerful left-footed drive that cannoned in off the crossbar.
In-form Ronaldo added the third for United six minutes before the final whistle after he cut ahead of the keeper to poke home Rooney's cross.
City finished with 10 men on the field after Italian striker Bernardo Corradi was sent-off in stoppage time for second bookable offense.
Elsewhere, Tottenham demolished struggling Charlton Athletic 5-1 at the White Hart Lane where Egyptian striker Ahmed Hossam 'Mido' came off the bench in the 76th minute.
Dimitar Berbatov's brace and goals from Teemu Tainio, Steed Malbranque and Jermaine Defoe led Tottenham to the big win. Egypt midfielder Hossam Ghaly was kept on the bench.
Charlton scored the consolation through Michael Dawson's own goal.