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 Barclays Premier League leaders over 10-man United.
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.
Lighting the fuse: Mario Balotelli strikes the ball towards the bottom corner of United's goal
No stopping that: United goalkeeper David De Gea attempts to get across but can't prevent the shot going in
Read all about it: Balotelli (left) celebrates by revealing a t-shirt that read 'why always me?'
Smells like team spirit: The Italian striker's City team-mates mob him after his opening goal
MATCH FACTS
Manchester United: De Gea, Smalling, Ferdinand, Evans, Evra, Nani (Hernandez 65), Fletcher, Anderson (Jones 66), Young, Rooney, Welbeck.
Substitutes: Lindegaard, Berbatov, Park, Fabio Da Silva, Valencia.
Booked: Evra, Anderson, Smalling, Welbeck
Sent off: Evans
Goals: Fletcher 81
Manchester City: Hart, Richards, Kompany, Lescott, Clichy, Toure Yaya, Barry, Milner (Kolarov 89), Silva, Balotelli (Dzeko 70), Aguero.
Substitutes: Pantilimon, Zabaleta, Nasri, Toure, De Jong.
Goals: Balotelli 22, 60, Aguero 68, Dzeko 90, 90+3, Silva 90+1
Booked: Kompany, Balotelli, Richards
Referee: Mark Clattenburg (Tyne & Wear)
Attendance: 75,487
Substitutes: Lindegaard, Berbatov, Park, Fabio Da Silva, Valencia.
Booked: Evra, Anderson, Smalling, Welbeck
Sent off: Evans
Goals: Fletcher 81
Manchester City: Hart, Richards, Kompany, Lescott, Clichy, Toure Yaya, Barry, Milner (Kolarov 89), Silva, Balotelli (Dzeko 70), Aguero.
Substitutes: Pantilimon, Zabaleta, Nasri, Toure, De Jong.
Goals: Balotelli 22, 60, Aguero 68, Dzeko 90, 90+3, Silva 90+1
Booked: Kompany, Balotelli, Richards
Referee: Mark Clattenburg (Tyne & Wear)
Attendance: 75,487
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 tonight.
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.
Seeing red: United defender Jonny Evans (right) is sent off by Mark Clattenburg after fouling Balotelli
Protest: United players surround referee Clattenburg after he sent off Evans in the second half
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.
Super Mario: Balotelli (right) pops up at the far post to score City's second goal
Three is the magic number: Sergio Aguero (left) followed Balotelli onto the scoresheet for the third goal
Having a ball: Argentina striker Aguero celebrates his strike in front of a stunned Old Trafford crowd
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.
Kneesy does it: Edin Dzeko (left) bundles in his side's fourth goal from close range
Still scoring: Spanish midfielder Silva slots his finish under De Gea (not seen) in injury time
Silva service: David Silva celebrates after scoring City's fifth goal to cap another outstanding show
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.
That does it: Dzeko rounds off the scoring with a cool finish for City's sixth goal
Six appeal: Dzeko shows the crowd the score and defender Aleksandar Kolarov celebrates
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.
Let's all do the Poznan: City fans celebrate their stunning win at the home of their rivals
Plenty to ponder: Sir Alex Ferguson was left to reflect on a devastating defeat
Game for a laugh: City manager Roberto Mancini enjoys his side's thrilling performance
Silva then broke clear to slide the ball under De Gea before the Spaniard released Dzeko to complete the rout.
Outnumbered: Wayne Rooney is crowded out by the City defence at Old Trafford
At full stretch: United midfielder Darren Fletcher is challenged by Micah Richards
I can't watch: Wayne Rooney reflects on a humiliating afternoon for the reigning Premier League champions