The Reds bossed a thrilling first half in which City skipper Vincent Kompany was contentiously dismissed, and had a three-goal lead at the interval through Wayne Rooney's brace and Danny Welbeck's acrobatic volley.
To their credit, City rallied after the break and pulled goals back through Aleksander Kolarov and Sergio Aguero, and almost snatched an injury-time leveller when Anders Lindegaard had to fist away a Kolarov free-kick.
The pre-match build-up was overshadowed by the shock announcement that Paul Scholes had reversed his retirement, signing a deal to return until the end of the season and immediately taking a place on the United bench.
Amid the furore, the news that Chris Smalling and Jonny Evans had returned from injury was almost lost. The former was fit enough to start at centre-back, with Phil Jones moving over to right-back, while Evans took a place on the bench.
Just as United could savour some rare good news on the injury front, the hosts found themselves deprived of several important players. Mario Balotelli and Edin Dzeko missed out through knocks, while Gareth Barry served a one-match ban and both Yaya and Kolo Toure reported for international duty.
Nevertheless, City began the game on the front foot, herding United back and coursing with confidence on their fruitful home turf. The Reds were given no time on the ball, evidenced in heart-stopping fashion when Aguero charged down Lindegaard's clearance. Fortunately for the Dane, the ball ricocheted wide of the target.