United's sixth straight league win came despite the soon-to-be-deposed champions going ahead through Sergio Aguero's eighth-minute opener.
Ashley Young and Marouane Fellaini scored to put United ahead at half-time, before goals by Juan Mata and Chris Smalling in a seven-minute span midway through the second half.
Aguero grabbed a late consolation for City.
City have now lost six of their last eight matches in a dreadful 2015 and now sit fourth, 12 points behind leaders Chelsea.
Fabregas rescuses Chelsea
Earlier, Cesc Fabregas scored an 88th-minute winner as Chelsea extended their lead to seven points with an unconvincing 1-0 win against a spirited QPR.
Spain international Fabregas, criticised for his drop in form since Christmas, burst into the box before dispatching Eden Hazard's lay-off to seal an undeserved victory in the west London derby.
QPR, embroiled in relegation battle, were the more dangerous team throughout and created a number of chances but were thwarted by visiting goal-keeper Thibault Courtois.
Chelsea dominated possession but, in the absence of injured forwards Diego Costa and Loic Remy, failed to register a shot on target before Fabregas's intervention.
Chelsea have 73 points from 31 games but have a game in hand of second-placed Arsenal, whom they play on April 26.
QPR remain 18th, two points behind Hull City - the side immediately above the relegation zone.
Results:
QPR 0-1 Chelsea
Manchester United 4-2 Manchester City
EPL top-scorers
19 Diego Costa (Chelsea)
Harry Kane (Tottenham)
17 Sergio Aguero (Man City)
Charlie Austin (QPR)
14 Olivier Giroud (Arsenal)
Alexis Sanchez (Arsenal)
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