The Latics had led thanks to a terrific goal from Leighton Baines, pressing his claims for a full England call-up as replacement for Ashley Cole who misses the next Euro 2008 qualifier against Israel through suspension.
The strike from 30 yards was a real eye-catcher, but just like last season, United came from behind with goals from Nemanja Vidic, Louis Saha and Ole Gunnar Solskjaer to snatch the points.
For Paul Jewell, it's now seven defeats as a manager at United's hands, and with only five points to show from their seven opening games, his forecast that Wigan face a tough season is looking spot on.
Beaten three times by United last season, including a 4-0 defeat in the Carling Cup final, Wigan were massive underdogs after a slow start to the season.
Both sides had had their preparations disrupted by international calls but Jewell was counting on the visit of Sir Alex Ferguson's team to kick-start Wigan's season.
There was a 20,000 plus crowd at the JJB stadium with Jewell naming an unchanged squad, while an ankle injury ruled out United's Cristiano Ronaldo, but Ryan Giggs was fit enough to take his place on the bench.
Wigan's goal came after four minutes when Baines followed up his wonder strike for the England under-21s against Germany last week with another super effort.
United were penalised for handball and from the free-kick, left-back Baines hammered an unstoppable shot beyond the keeper's reach to register his first Premiership goal and only the second of his Wigan career.
United had a let off when Edwin Van der Sar appeared to handle outside the area but it went unpunished, and there was more danger when the Reds conceded another free-kick in an almost identical position.
This time Denny Landzaat tried his luck but curled the shot wide.
Solskjaer was on target for United but did not seriously test Chris Kirkland and Michael Carrick fired another over the bar.
A touch of magic from Wayne Rooney inside the box almost levelled it but to Wigan's relief the England star's strike on the turn came back off the crossbar.
Gary Teale volleyed just wide at the other end and the Latics had United on the back foot again when Emmerson Boyce raced clear down the right. Midfielder Paul Scharner arrived at the back post but failed to get any power or direction on the shot.
Ferguson sent on Giggs to replace Wes Brown, and United made a positive start to the second half with Solskjaer carving out a chance but putting it over the bar from close range.
United blew a great chance when Saha wrong-footed Wigan captain Arjan De Zeeuw to earn himself a clear sight of the target, but with Kirkland making the angle difficult for the French star, he hit the left-foot shot just wide.
United's pressure finally paid off after 62 minutes when Serbian defender Vidic climbed high to meet the corner from Giggs to head his first goal for the club.
Four minutes later United were in front after cashing in on a Wigan mistake when Teale gave the ball away.
Rooney swept in the cross from the left and Saha struck from the edge of the six-yard box and the shot went in off the foot of the post.
Rooney - desperate to improve on his record of one goal in 16 games - found luck had deserted him again when he chipped one over the bar and Kirkland prevented further damage blocking a Saha shot with his legs.
But United added a little extra polish to the scoreline when Solskjaer tucked away the third in stoppage time.