Ole Gunnar Solskjaer's men will be looking for a response when they meet their nearest neighbours after the disastrous collapse against Everton on Sunday.
They welcome City to Old Trafford with Pep Guardiola's team needing to win to keep the destination of the title in their hands. Lose or draw and it'll be advantage to Liverpool.
It promises to be a typically dramatic contest with no quarter likely to be asked or given.
Here's everything you need to know:
Manchester United need a response after the abject performance against Everton but could scarcely have wished for a harder test with the title-chasing champions coming to town.
Motivation shouldn't be a problem, however, with Solskjaer sure to send them out on full cylinders from the off. Expect them to get after City from the get go with United's team selection in the middle of the park likely to be key.
The in-form Scott McTominay will surely be tasked with getting around one or both of David Silva and Bernardo Silva in an attempt to stop City ticking. City, for their part, only really know one way to play and will look to start fast once again with their habitual early goal potentially crucial.
Going the other way Fernandinho, having been eased back in, should start as Guardiola looks to protect against the damaging raft of counter-attacks that blighted his side against Tottenham over the last fortnight.
In attack the decision between the energy of Ilkay Gundogan and the explosion of Leroy Sane is likely to be the Spaniard's toughest call.
City need the win and if they turn up with the required intensity then the quality gap between the sides should be enough for them to get it. 1-2, a nervy but massive away win.
What time is it and how can I watch it?
The game kicks off at 8pm on Wednesday at the Old Trafford.
The game will be shown live on Sky Sports Main Event and Sky Sports Premier League.
We will be live blogging the game too, of course.
Captain Ashley Young could return at full-back after being left out from the start against Everton. Ander Herrera could also return in the middle of the park where Nemanja Matic could be the man to make way.
Defenders Antonio Valencia and Eric Bailly remain sidelined and will miss out.
Kevin De Bruyne will miss the game after limping out of the clash with Tottenham on Saturday with a hamstring injury. He could miss the remainder of the season as the club await further test results.
Benjamin Mendy is working his way back to full match fitness and could return in place of Oleksandr Zinchenko at left-back.
Manchester United: De Gea, Young, Lindelof, Smalling, Shaw, Herrera, McTominay, Pogba, Lingard, Lukaku, Rashford
Manchester City: Ederson, Walker, Stones, Laporte, Mendy, Fernandinho, Silva, Silva, Sterling, Aguero, Sane
Manchester United 6/1
Manchester City 40/85
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