The EFL Cup fourth round derby provides City with the perfect chance to return to winning ways.
Having already beaten cross-town rivals United this season in the Premier League, City will go into the game with confidence despite a tough run of results.
Club journalist Rob Pollard takes a look at four things to look out for ahead of the game.
1 Reds motivation
City’s 2-1 win over United at Old Trafford in September – their 50th derby victory - was one of the most comprehensive performances boss Pep Guardiola has masterminded during his three-and-a-half months in charge.
The scoreline may suggest a tight affair – but for the first 40 minutes, City were far superior to their opponents, playing with a verve and fluidity the hosts simply couldn’t match.
It’s a result and performance that hurt the Old Trafford side – and they will see Wednesday’s EFL Cup game as the opportunity to exact revenge.
Mourinho, in particular, will be desperate for a positive result. He has managed three wins in 17 matches against Guardiola.
2 Gruelling fixture schedule
Guardiola is a manager whose career has seen him use a core of players regularly, preferring continuity to rotation.
But City are in the midst of a difficult sequence of fixtures. They play West Brom three days after the game with United, before a crucial Champions League fixture against Barcelona on Tuesday.
It will be interesting to see whether Guardiola decides to make changes to his side in order to keep things fresh for the trip to the Hawthorns this weekend.
3 De Bruyne factor
De Bruyne took a blow to the calf during the 1-1 draw with Southampton and is unavailable for the game with United.
The Belgian has been one of City’s most impressive players this season and has consistently looked a threat in the No. 10 role, designed by Guardiola to give him freedom to create.
He will be a significant loss – but Guardiola is stacked with midfield talent in his squad and should be able to fill the void.
4 Old Trafford confidence
There was a time not so long ago when a City win at Old Trafford felt like a distant dream.
Between 1976 and 2008, City didn’t pick up a single victory at the home of their local rivals.
Things have changed dramatically in recent times. City have managed four wins and a draw from their last six visits – and the fear and panic that used to grip Blues supporters before derby matches is gradually ebbing away.
City now go to Old Trafford feeling confident they can get something.