The England striker should have marked the game with a hat-trick only to miss a 61st minute penalty with a tame shot.
Shell-shocked Aston Villa, meanwhile, endured a nightmare 90 minutes and finished the game with only nine players after Nigel Reo-Coker and goalkeeper Scott Carson were sent off in the second half.
United, however, had to stage a tremendous recovery after conceding their first goal in 611 minutes when Gabby Agbonlahor put Villa ahead after only 13 minutes.
But the goal only injected more determination into United's play and the outcome was hardly a surprise as Villa surrendered increasing pressure generated by swiftly executed moves in which Nani was a key operator.
The result was hardly a surprise either as Villa Park is home from home for United who stretched their unbeaten run against the Midlands club to 13 games. But it was Villa's first home defeat following four successive wins.
Villa's night of woe was completed in the second half when they had Reo-Coker sent off for a second yellow card to be followed shortly afterwards by goalkeeper Carson for bringing down Carlos Tevez.
Earlier, Villa's confident young guns had not been over-awed by Manchester United in the opening stages. Once again they demonstrated their rich vein of skilful play to pose considerable problems for the Old Trafford crew.
Their only mistake was the audacity of scoring when they breached United's defensive fortress early in the game.
They had an early scare when referee Rob Styles awarded an indirect free-kick well inside Villa's penalty area but a complicated move involving Rooney and Giggs badly misfired although the United pair certainly atoned later in the game.
The game exploded into life in the 13th minute when Villa took their shock lead. Ashley Young, who enjoyed an outstanding match with his dazzling runs, produced a left-wing cross which Agbonlahor deftly headed past Edwin Van der Sar after popping up in front of Wes Brown.
But it quickly became apparent that United were not going to be in arrears for too long. They slowly began to lift the pace with some scintillating football which had the likes of Zat Knight struggling in the middle of Villa's defence.
The equaliser duly arrived in the 36th minute when Rooney, who had earlier failed to hit the target with a mis-hit shot on the turn, had the easiest of chances when he coolly slipped a low cross-shot home from Nani's right-wing cross.
If anyone needed confirmation that Rooney is back to his lethal best in front of goal it occurred when he collected a Tevez pass to finish with a razor sharp, low shot to the right of Carson. The goal even had Sir Alex Ferguson jumping out of the dug-out with joy.
Sir Alex was even more pleased a minute later when a Nani corner was headed goalwards by Tevez only to be cleared off the line by Young. Rio Ferdinand, following up, saw his effort sliced into the net by the unfortunate Craig Gardner.
Things went from bad to worse for Villa in the second half. Reo-Coker, who had been booked eight minutes earlier, was sent off for a tackle on Anderson in the 60th minute.
Carson then brought down Tevez to concede the 66th minute penalty which substitute goalkeeper Stuart Taylor had little difficulty in saving.
But Taylor had no chance when Martin Laursen headed Ryan Giggs' shot into the net in the 75th minute for the fourth goal.