Robbie Blake's volley stunned the reigning champions on Wednesday night before Michael Carrick blew a chance to equalise by missing a penalty.
Having lost three valuable points early on in the title race, Sir Alex Ferguson will know that emerging from the DW Stadium with three points is essential.
History favours United, as they have beaten Wigan on each of the nine occasions the two sides have met, with eight of those wins coming in the Premier League.
The Latics are also looking to rebound from a disappointing loss as they play at home for the second time in four days.
New manager Roberto Martinez was blessed with the perfect start to his reign when his side defeated Aston Villa 2-0 on the opening day.
But newly-promoted Wolves brought them back down to earth on Wednesday when Andy Keogh inspired Mick McCarthy's team to a 1-0 away win.
Wigan did threaten to spoil the Red Devils' title party the last time the two teams met, when Hugo Rodallega fired them into an early lead.
But goals from Carlos Tevez and Carrick turned the match around to maintain United's perfect record and virtually assure them of a third consecutive championship.
Team NewsThe reigning champions have suffered a fresh blow going into the match with the news that Rio Ferdinand will be ruled out for up to a month due to a thigh injury.
The England defender has missed the start of the Premier League campaign but had hoped to make a quick return to the side.
There is more positive injury news for United as Ferdinand's partner at centre-back, Nemanja Vidic, has been given the all-clear to start after missing the first two games of the season with a calf problem.
The Serbia international has also had his return thwarted by an ankle injury but is now ready for action after a period of uninterrupted training.
Wigan winger Charles N'Zogbia is a fitness doubt for the contest as he is currently struggling with an ankle injury.
The French player picked up a knock against Villa but was passed fit to play in the midweek contest against Wolves.
But the injury has not gone away since and N'Zogbia is now rated as 50/50 for the clash with champions Manchester United.
Possible Starting XIsWigan: Kirkland, Melchiot, Scharner, Bramble, Figueroa, Brown, Thomas, Koumas, Gomez, Sinclair, Rodallega.
Man Utd: Foster, O'Shea, Evans, Vidic, Evra, Valencia, Anderson, Carrick, Giggs, Rooney, Berbatov.