The Red Devils go into the game a point behind bitter rivals City and three points adrift of table-toppers Chelsea.
Here is a complete preview of the 3pm (GMT) kick-off, with team news, projected lineups and more.
Manchester United's new destructive duo of Shinji Kagawa and Robin van Persie is set to be ruled out this weekend after both picked up knocks during the international break.
Kagawa was rested for Japan's World Cup qualifier against Iraq after picking up a back problem in the game against UAE.
According to Goal.com, the 23-year-old trequartista has been suffering from a recurring back injury since he started his professional career, and is a big doubt for the Wigan game with the club's medical staff keen to get to the bottom of the issue.
Van Persie is also unlikely to play after being subbed at half-time in the Netherlands' 3-1 win over Hungary with a thigh injury.
And via the same Goal.com article, United are reportedly placing Van Persie under a 48-hour assessment, with the club going for a safety-first policy thanks to lengthy injury history.
Both have apparently been rested with Wednesday's UEFA Champions League opener against Galatasaray in mind.
Wayne Rooney, Darren Fletcher, Phil Jones, Chris Smalling and Jonny Evans are also ruled out through injury.
Wigan Athletic manager Roberto Martinez will be able to call on the services of key midfielder James McArthur against Manchester United, after the Scotland star was ruled out during the international break with a back injury.
The 24-year-old wasn't called up for his country's matches after a back problem left him far from full fitness, and manager Martinez said of injury (h/t SkySports):
James has been through a very demanding start to the season, because after an hour or so on the pitch his back begins to stiffen up and against Chelsea and Stoke he tired towards the end of the game when the tempo was high.
But he has such a strong mentality which allows him to be available and I think the two-week period we've had has helped him with his full recovery.
Chilean winger Jean Beausejour looks set to miss the game however after tearing his hamstring in the 2-2 home draw with Stoke City.
Apart from Beausejour, Wigan will head into the game with all their key players at full fitness.
Manchester United go into the game against Wigan in good attacking form, though anything but in defence.
Having lost 1-0 in the opening match away to Everton, United looked sharp and creative in the final third as they beat Fulham 3-2 at home, and again when they beat Southampton away by the same scoreline.
However, it was a different story in defence, with the lack of a solid partnership, and therefore understanding, in central defence hurting the Red Devils.
The lack of match practice for Nemanja Vidic, who has just returned from a nasty knee injury, also doesn't help matters for manager Sir Alex Ferguson, as the Serb is yet to fully re-adjust to Premier League pace and has yet to build an understanding with either of the two goalkeepers, David de Gea and Anders Lindegaard.
But being the only fully fit senior centre-back United have, with Rio Ferdinand's fitness fluctuating, the Red Devils can only hope Vidic returns to his old form pronto.
Wigan Athletic head into their glamour league fixture at Old Trafford in better form than their points total might suggest.
Despite losing 0-2 at home to Chelsea on the opening Premier League weekend, the Latics had more possession than the Blues and more than double the amount of total shots.
And away to Southampton, they punished the Saints for their wasteful finishing and took advantage of their defensive mishaps to record a clinical 2-0 win.
In the 2-2 draw at home to Stoke City, Roberto Martinez would've been quite disappointed not to get three points.
Wigan had 69 percent of the possession, passed the ball around 14 percent more accurately than their opponents (h/t WhoScored.com) and generally dominated the visitors.
They won't be expected to get anything out of the game against Manchester United, but that could work in their favour, especially seen how United have struggled with complacency over the past few seasons.
Antonio Valencia will be a key player for Manchester United this Saturday against his former side.
The Ecuadorian winger has long been a model of consistency, with his crossing, link-up ability and eye for a key pass virtually unparalleled in the Premier League.
Against Wigan's error-prone centre-backs Ivan Ramis and Antolin Alcaraz, as well as the rather slow left-back Maynor Figueroa, Valencia's pace and vision to spot runs through the defence will come in very handy and could see him claim a few assists, especially as Valencia makes a greater number of key passes than any of Wigan's defenders do interceptions.
With Wayne Rooney, Robin van Persie and Shinji Kagawa all out, Javier Hernandez will finally get his chance to shine this season.
His style is suited to get goals against the Wigan defence, with his very good movement set to see him have a ton of scoring opportunities against the poor man-marking ability of the centre-backs.
With Rooney and Kagawa out, it'll be up to Welbeck this Saturday to be the link between midfield and attack. A player with exceptional passing accuracy in the final third, the England international's link-up play could see him get a goal or assist, or both.
Franco di Santo
If there's one player who's most likely to capitalise on Manchester United's defensive frailties, it's former Chelsea striker Franco di Santo.
The 23-year-old is looking like an improved player from his seven-goal campaign last season, with two in three games already this term.
A player with the ability to find the target from small pockets of space in the final third, Di Santo could grab a goal or two if he isn't closed down quickly enough.
Shaun Maloney is an experienced winger, hot on form, who'll likely be up against a fairly inexperienced right-back in Rafael da Silva.
That combined with his ability to draw fouls and Rafael's somewhat frequent poor decision-making and tendency to make rash challenges could either see Maloney be in for a one-on-one with the United goalkeeper, or see him win a penalty for his team.
It's no wonder manager Roberto Martinez was delighted to have James McArthur fit again. The Scot is the midfield maestro that keeps Wigan ticking, with his very good long-range passing vital in a lot of his side's goals.
He'll need close attention from United's midfield, otherwise he could set Wigan up for some very threatening attacking opportunities.
Here are some key stats and facts ahead of the match at Old Trafford:
- Robin van Persie will be missed: he's scored four goals in three games, and four from just six shots on target.
- The flying Dutchman has also netted 52 goals in his last 58 league matches.
- Manchester United have more possession than any other Premier League team in their away matches (61.5 percent), but at home retain the ball less than Wigan do.
- Before their defeat last April, United had won every competitive fixture they've played against Wigan.
- The Latics are likely to get a red card at Old Trafford, having received three in their last two visits to the red side of Manchester.
- But Roberto Martinez's men go into the match on the back of six wins in their last nine Premier League matches.
- Then again, Wigan have failed to score in eight of their last ten matches with Manchester United.
- Wigan have scored four goals this season—one each from open play, a counter attack, a set-piece, and from the penalty spot.
- United have scored four from open play and two from set pieces.
David de Gea will be recalled to the Manchester United lineup after being dropped for the Southampton game after his error against Fulham, as confirmed by manager Sir Alex Ferguson.
While with Wayne Rooney, Shinji Kagawa and Robin van Persie all out, Javier Hernandez will no doubt get his chance to lead the line, with Danny Welbeck set to play the support-striker role thanks to his excellent final-third link-up play and great passing accuracy between the opponent's defensive and midfield lines.
Nani could find himself on the bench again, having seemingly fallen out of favour at Old Trafford thanks to an ongoing contract dispute.
Ashley Young looks set to play instead opposite Antonio Valencia, having sat out England's last two matches with a knee injury.
With most of their key players fully fit, Wigan Athletic look set to field a full-strength lineup against Manchester United as they seek to play their most experienced players.
Arouna Kone and Franco di Santo will again have another chance to build up a partnership, while the return of James McArthur means the likes of Shaun Maloney will have a greater chance to express themselves in the final third without the constant need to track back.
In defence, Martinez is set to continue with the back three of Gary Caldwell, Antolin Alcaraz and Ivan Ramis, with the full-backs given license to get forward.
Manchester United 2-1 Wigan Athletic
Manchester United should win at home to Wigan Athletic this weekend, but with their defensive far from being on top form, it could end up being a close game.
Danny Welbeck and Javier Hernandez will be good replacements for Robin van Persie, Wayne Rooney and Shinji Kagawa, and with both needing to grasp their chances this weekend, one if not both players could end up on the scoresheet.
Wigan also look like scoring however, thanks to United's poor defence and the form of players like Shaun Maloney and Franco Di Santo.
It should be a closer match than some predict, but the Red Devils will seemingly have too much quality on the wings and in attack for their visitors to handle.