Arsene Wenger will be demanding a response from his team after the 5-1 loss at Anfield, while David Moyes will seek improvement after a desperate draw with Fulham on Sunday.
The Scot is facing mounting calls to change United's attacking approach following the disappointment of being held to a 2-2 draw against bottom side Fulham at Old Trafford on Sunday.
United made more crosses (81) in a single game than any other Premier League team since the start of the 2006-07 season during the Fulham encounter, but was left to rue its wastefulness in the final third.
The fact that Wednesday's game is not a clash between two title rivals - as is traditionally the case - speaks volumes of United's continued struggles during Moyes' first season in charge.
The defending champion trails second-placed Arsenal by 14 points and have lost its last three away games in all competitions.
Yet this is a fixture in which United has a decent recent record.
Unbeaten in its last five games against Arsenal and having suffered just one defeat in its previous five visits to the Emirates in all competitions, United knows how to grind out results against Arsene Wenger's men.
But Moyes must inspire a much-improved performance if his players are to prevent Arsenal bouncing back from its 5-1 thrashing at Liverpool on Saturday.
The ease with which Liverpool scored four times in the opening 20 minutes will concern Wenger and the club's supporters.
Humiliation at Anfield coupled with Chelsea's 3-0 win over Newcastle United saw Arsenal knocked off top spot in the Premier League.
Wenger, though, is confident of a response against United, pointing to Arsenal's fine home form as the reason behind his optimism.
Indeed, Arsenal lost only twice at the Emirates in the Premier League in 2013 and is 11 games unbeaten at home in the league - a run that stretches back to Sept. 1.
There is no question that Arsenal's success has been built from the back, with the team keeping four successive clean sheets on home soil in the Premier League and seven shutouts in its last eight league outings at the Emirates.
One United player capable of ending Arsenal's proud defensive record will need no introduction to Wenger, though.
Former Arsenal striker Robin van Persie has scored eight times in his last nine Premier League games, including the only goal when the two sides met at Old Trafford in November.
Van Persie has netted in each of the three games against his old club since joining United and will be keen to silence the boo-boys as he braces himself for another hostile reception from the Emirates faithful.
Marouane Fellaini (groin) and Jonny Evans (calf) are likely to miss out for United, although Phil Jones may return from concussion.
Mathieu Flamini serves the final game of his three-match ban for Arsenal, which will again be without Aaron Ramsey (thigh), Thomas Vermaelen (knee) and Kim Kallstrom (back).
Jack Wilshere returned to the side at Liverpool following an ankle injury and suffered no ill-effects, so will continue in midfield.