Substitute Cristiano Ronaldo scored twice in four minutes as Manchester United extended their lead at the top of the Premiership to four points.
Ronaldo had an immediate impact with two quick goals
Ronaldo came on at the break and headed United in front with his first touch before scoring a rebound after Chris Kirkland parried his penalty.
The spot-kick was awarded after Gary Teale fouled Ji-Sung Park.
Ole Gunnar Solskjaer then finished with his right foot before Leighton Baines scored a late penalty for Wigan.
United took to the field for the match shortly after rivals Chelsea had been held at home to Reading.
It was a very different United side to that which defeated Aston Villa on Saturday - with Ronaldo, Rio Ferdinand, Louis Saha, Gary Neville and Ryan Giggs either omitted completely or relegated to the bench.
Nonetheless, the home team set about their work with great intensity and were soon peppering Kirkland's goal.
Park cut inside from the left flank and shot narrowly wide after three minutes, while Rooney came within inches of scoring shortly afterwards.
The striker seemed certain to convert Wes Brown's low, powerful cross but the ball struck Kirkland and slowly dribbled goalwards.
Kirkland scrambled after the ball and eventually cleared the danger while a disbelieving Rooney appealed in vain that it had crossed the line.
The Latics keeper later saved from Mikael Silvestre and saw a Rooney strike flash just wide of his goal.
Rooney, who played with great conviction, collected a Darren Fletcher through ball just after the half-hour mark and shot across goal on the turn - his effort missing by inches.
But United's play had become increasingly fractured as Wigan did a reasonable job of stymieing their opponents - and the home crowd fell silent as the first half wore on.
They almost had something to cheer just before the break but Kirkland held on to Solskjaer's diving header.
Ferguson's decision to introduce Ronaldo for Fletcher paid dividends within two minutes of the restart when the Portugal international headed home Paul Scholes' corner.
Ronaldo was left completely unmarked to score his ninth goal of the season.
And Ronaldo struck again four minutes later, stroking the ball home after Kirkland parried his initial penalty kick.
Teale, guilty of the crude hack that led to the penalty, was withdrawn minutes later as Old Trafford found its voice - the United supporters celebrating an extension of United's lead at the top of the Premiership.
Solskjaer latched on to a Rooney header and tucked the ball across goal and into the bottom corner to further add to the party atmosphere.
Matt Jackson almost pulled a goal back for Wigan but directed his header straight at Edwin van der Sar before the luckless Rooney hit the crossbar at the other end from 12 yards.
Wigan scored their consolation goal with virtually the last kick of the game, Baines drilling his penalty down the middle of the goal after Silvestre had fouled David Wright.
Manchester United manager Sir Alex Ferguson:
"I had a feeling he would change the game.
"We needed a quick response to what happened in the first half and Cristiano is in such great form, it was an obvious move.
"He lit up the crowd and got us two goals, which is just what we were looking for."
Wigan manager Paul Jewell:
"You cannot give any of the top teams free goals. That is two games in a row - Chelsea and Man Utd - where we have conceded from a corner.
"The disappointing thing is not that we have lost but the manner in which we conceded the goals.
"We were always going to be up against it but at least we showed a bit of spirit and got a goal."
Man Utd: Van der Sar, Brown, Vidic, Silvestre, Evra (Heinze 70), Fletcher (Ronaldo 46), O'Shea, Scholes (Richardson 62), Park, Solskjaer, Rooney.
Subs Not Used: Kuszczak, Saha.
Goals: Ronaldo 47, 51, Solskjaer 59.
Wigan: Kirkland, Boyce, Jackson, Hall (Skoko 60), Baines, Teale (Cotterill 52), Johansson, Wright, Kilbane, Todorov, Heskey.
Subs Not Used: Pollitt, Landzaat, Cywka.
Goals: Baines 90 pen.
Ref: M Riley (W Yorkshire).