Controversial striker Mario Balotelli provided the spark as City stormed Old Trafford to humiliate rivals United.
Hours after more headlines about his off-field antics following a fire at his home, Balotelli struck twice to set up a convincing win for the visitors.
Balotelli also won the free-kick which led to a straight red card for United defender Jonny Evans before Edin Dzeko struck twice and Sergio Aguero and David Silva added to the tally.
United claimed a consolation with a fine goal from Darren Fletcher 10 minutes from time but they were ran ragged in the dying moments as City struck three times after the 88th minute.
City's stunning victory not only lifted them five points clear of United and underlined their title credentials - but shattered a host of statistics.
In recording only their second win at Old Trafford since 1974, City inflicted United's first home defeat since April 2010 and ended their run of 19 consecutive home league wins.
It left the watching Glazers, United's owners, hoping for better luck as they flew to Wembley by private helicopter to watch their other team, the Tampa Bay Buccaneers, in the NFL on Sunday night.
Balotelli had returned to the side after suspension in midweek as one of six changes.
United showed similar rotation from their Champions League win over Otelul Galati with fit-again defender Rio Ferdinand among those to come in while Phil Jones and Nemanja Vidic dropped out.
It was the hosts who made the early running with Ashley Young twice testing Micah Richards down the left, winning a free-kick and a corner.
United threatened again when Young bent in another free-kick but Balotelli was back to head clear.
Wayne Rooney went down in the box under a challenge from Vincent Kompany but referee Mark Clattenburg saw nothing untoward.
Despite their quieter start, it was City who took the lead after 22 minutes through Balotelli.
Silva fed Milner and the midfielder pulled the ball back for Balotelli to place a low, first-time shot beyond the reach of De Gea from 18 yards, finding the right corner.
He marked the goal with self-deprecating humour by lifting his shirt to reveal a T-shirt saying, "Why Always Me?".
United responded but Anderson and Rooney both shot straight at Joe Hart.
United had another good chance when Rooney pulled the ball back from a Young cross but Evans badly miskicked.
Kompany was booked for bringing down Danny Welbeck as United tried to launch another counter-attack but City held firm until the break.
United's problems then increased considerably as Evans was sent off within two minutes of the restart for denying Balotelli a goalscoring opportunity.
Balotelli stayed on his feet until crossing the 18-yard line as Evans pulled back his arm but Clattenburg awarded a free-kick outside the area and then showed the defender the red card.
United survived the resulting set-piece and breathed again shortly afterwards when Clattenburg gave nothing after Richards collided with Anderson and appealed for a penalty.
Another chance came as Balotelli picked out Aguero with a deep cross but the Argentinian failed to connect with a volley and Richards missed the target.
Young went close as United countered but his mishit first shot rebounded off Milner and he was rushed into guiding a second attempt wide.
United applied more pressure with Rooney shooting at Hart again but City made their numerical superiority count with a well-worked second goal for Balotelli just before the hour.
Silva caught the home defence with a brilliant ball for Milner inside the area and Balotelli arrived unmarked to turn in his cross for a sixth goal in five games.
Chris Smalling then made a vital interception in front of goal as Balotelli threatened to grab a hat-trick.
City were in complete control and claimed a third after 69 minutes as Milner played Richards into space on the right and he duly squared for Aguero to slide home from six yards.
Roberto Mancini decided to take off Balotelli with 20 minutes remaining and he left the field quietly to take the congratulations of his team-mates on the bench.
His replacement Dzeko almost scored a fourth City goal within moments of entering the field with a low shot which rolled just wide.
Dzeko had another chance as United were caught out again but De Gea produced a fine save.
United clawed one back as Fletcher curled in a fine effort from long distance but City upped the tempo with three more in the closing minutes.
Joleon Lescott was free to cross at the back post as a free-kick was flicked on and the ball rebounded in off Dzeko.
Silva then broke clear to slide the ball under De Gea before the Spaniard released Dzeko to complete the rout.