Manchester United boss Jose Mourinho will look for a response from his side, after Sunday afternoon's Premier League mauling versus former employers Chelsea at Stamford Bridge.
Wednesday night represents the perfect opportunity for that with Pep Guardiola's Manchester City now without a win in five games in all competitions.
With both sides in indifferent form in what is still derby encounter, what starting XI will Mourinho opt for?
Shaw to return as Blind reverts to centre-back
Whilst no surprise, the news that centre-back Eric Bailly has been ruled out until at least Christmas, is nevertheless a blow for The Red Devils.
With full-back Luke Shaw not having started a league game since September, the former Saints man is expected to slot in a left-back, as Daley Blind shifts to a central defensive role. The Dutchman will be partnered by Chris Smalling.
On the opposite flank, Matteo Darmian played in United's 4-1 win over Fenerbahce in the UEFA Europa League last Thursday. The Italian may come in for Antonio Valencia.
Despite not having kept just four a clean sheets in total this season, David de Gea will likely be preferred to Sergio Romero in goal.
Pogba to continue in midfield
For the world's most expensive player, Paul Pogba's return to Manchester has began with something of a whimper.
With the Frenchman's performance against Leicester City his only occasion to shine versus top opposition thus far, Pogba has been under the microscope with his £100m price tag. The 23 year-old was invisible against The Blues, but will aim to be the key man in midfield versus United's cross-city rivals.
With calls for Michael Carrick to be re-installed to partner Pogba and with Marouane Fellaini injured, Mourinho is set to start the veteran Englishman.
Mata to be recalled, Ibrahimovic seeks goals
In attack, Juan Mata is set to be recalled. The Spaniard was brought on at half time in West London, as United were left without a creative outlet.
Wayne Rooney could return if he passes a late fitness test on a muscle injury, but may still have to settle for a place on the bench. Anthony Martial - despite a poor start to the campaign - will likely also get another chance to redeem himself versus The Citizens.
Jesse Lingard is expected to start on the right of an attacking three.
As Zlatan Ibrahimovic's goal drought continues, the talismanic Swede is nonetheless set to to start at Old Trafford.
Having scored on his debut for Manchester United in the Community Shield versus The Foxes and scoring four goals in as many league games at the start of the campaign, the 35 year-old is now without a goal in 360 minutes of game time in all competitions.
The clash with Manchester City, therefore, could be the perfect platform for Ibrahimovic to return to form.
Predicted XI: de Gea; Darmian, Smalling, Blind, Shaw; Carrick, Pogba; Lingard, Mata, Martial; Ibrahimovic.