It seemed the Red Devils would have to settle for a point after Cristiano Ronaldo's brace had only proved enough to keep United level against a Villa side that thoroughly deserved a lead provided by John Carew and Gabriel Agbonlahor.
But Macheda, a former member of the Lazio academy who arrived at Old Trafford in 2007, was to have the last word.
At exactly the same moment as Yossi Benayoun struck for Liverpool at Fulham on Saturday, Macheda turned onto Ryan Giggs' low pass before unleashing a stunning shot that curled past Brad Friedel and sent Old Trafford into ecstasy.
With Rio Ferdinand's groin injury failing to ease in time for him to be considered, United were without their first-choice defenders and their first-choice strikers amid six missing men that included Wayne Rooney.
Gary Neville's first appearance for two months was expected to come at right-back, so it was something of a surprise to see him line up alongside Jonny Evans in the centre of United's defence.
Carew's eyes certainly lit up, given his vast height advantage, which he duly exploited to the full.
On the back of an eight-match winless streak, Villa's confidence was a bit fragile too but their dominance in the 14 minutes before Ronaldo's wonder-goal provided enough evidence for them to retain self-belief even after they had gone behind.
During that opening flurry of attacks, Fletcher kneed a Carew header onto a post and Agbonlahor sped clear of Neville only to fail in his quest to find a team-mate with a low cross.
It is difficult to understand why a team that swept all before it for virtually three months should suddenly appear to be so poor.
Beyond question is the individual ability they possess, although the brutal nature of Ronaldo's 19th goal of the season still took the breath away.
Normally the kind of opportunity provided when James Milner and Friedel got themselves into a muddle, forcing the Villa keeper to handle a back pass, could be a bit of a negative given its proximity to the opponents' goal. Not on this occasion.
Ryan Giggs brushed the ball to his illustrious young team-mate, who sent it over the wall and into the roof of Friedel's net in a flash.
A sense of calm should have spread across home ranks. Instead, Villa merely came again.
Showing the form that established them in the Champions League positions at Arsenal's expense by the end of January, Agbonlahor and Ashley Young terrorised the United defence.
Edwin van der Sar was called upon to keep Villa out on three occasions but there was nothing he could do to deny Carew when Gareth Barry wriggled his way into space by the touchline.
The Norwegian crept between Neville and O'Shea to steer a deft header into the bottom corner.
Ferguson responded by putting Neville back to full-back, giving up the unequal struggle of competing with Carew. He also urged the United fans to make more noise, indicating a fear that talent on its own was not going to be enough.
The response was patchy and failed to curb Villa's enthusiasm.
Ronaldo excels at many things. Chasing back is not one of them. And when he gifted possession to Stiliyan Petrov inside the visitors' half just before the hour, he allowed the Bulgarian to sweep upfield unopposed.
Agbonlahor hung around waiting for the cross Petrov presented Carew with the opportunity to supply, then rose majestically to find the bottom corner, just as his strike partner had done earlier.
Ferguson's response was to introduce 17-year-old Macheda, which in itself said something about United's plight.
It did however bring an immediate improvement and when Michael Carrick exchanged first-time passes with Giggs on the edge of the Villa box, he then presented Ronaldo with a lay-off.
The world player of the year did not have a lot to aim at but he found the one small gap Friedel was unable to cover.
Still, when Friedel denied Danny Welbeck two minutes from time, it seemed United would have to settle for a point.
Macheda, however, had other ideas.
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