Former Arsenal boss Arsene Wenger enjoyed and endured many memorable showdowns with United - and against Jose Mourinho, for that matter - but the midweek showdown will be Unai Emery's first taste of the fixture.
The Gunners go into the match off the back of a rousing 4-2 win over Tottenham Hotspur in the North London derby, though, whereas United are without a victory in their last three league games and sit eight points adrift of their fourth-placed opponents.
Here, Sports Mole selects a combined XI from the two squads, using only players who are available for the match.
The goalkeeper is one of the few easy choices in this XI, with David de Gea still regarded as arguably the best in the world in his position, despite the ongoing troubles of those in front of him. Bernd Leno is comfortably second best in that selection.
Arsenal do dominate the defence in front of him, although it is not exactly a star-studded collection to choose from. Doubts over the fitness of Chris Smalling mean that Rob Holding earns a place at centre-back alongside Shkodran Mustafi, with the duo having begun to forge a decent partnership for the Gunners - albeit one which is still prone to errors now and again.
Hector Bellerin's status as a specialist right-back sees him selected ahead of Ashley Young and Antonio Valencia, but there is a United representative on the opposite flank with Luke Shaw taking advantage of an injury to Nacho Monreal and beating off competition from Sead Kolasinac.
Lucas Torreira enhanced his burgeoning reputation with a goalscoring performance during the North London derby and is a sure-fire inclusion in the midfield, but Nemanja Matic has endured some poor form so far this season and is only included in this XI due to Granit Xhaka being suspended for Wednesday's match.
Using Arsenal's 4-2-3-1 system means that Paul Pogba is pushed into a more advanced position than he usually plays, but he has the game-changing ability to prove effective there, particularly considering the dynamic nature of those around him. Mesut Ozil is a doubt for Wednesday's match, while Aaron Ramsey was in contention for a place in this team but is struggling to even get into the Arsenal XI at the moment.
Anthony Martial's performances throughout the season are enough to win him a spot despite his recent goalscoring streak drying up, as the likes of Henrikh Mkhitaryan, Alexis Sanchez, Jesse Lingard, Alex Iwobi, Marcus Rashford and Juan Mata all miss out.
There is no doubt over Pierre-Emerick Aubameyang's place, though, with his brace against Spurs at the weekend meaning that he is now the Premier League's top scorer and has struck 20 goals in just 27 league games for the club.
With Aubameyang on the left, the centre-forward position comes down to a straight shootout between Alexandre Lacazette and Romelu Lukaku. Lukaku has been in poor form for most of the season, despite ending his goal drought at the weekend, so Lacazette gets the nod despite facing a race against time to be fit for this match.