It is nearly three years since they lost three games in a row, which means the stakes could hardly be higher.
Win, and you reverse the momentum that has been going City's way, remind them who is boss and heap pressure on them in the Premier League.
Lose, and the season risks drifting away completely as City, with superior playing personnel, continue their charge towards a domestic double.
Personally, I think this game has come at the perfect time for United - though I may not be saying that on Sunday night.
They have underachieved badly in recent games, with a lack of leadership from players like Rio Ferdinand, Patrice Evra, Michael Carrick and Wayne Rooney at Newcastle.
An easier Cup tie would give United a chance to idle through - and in fact they have struggled desperately in such games against Exeter, Burton and a third-tier Leeds side in recent years.
As it is, the big names have no choice but to man up. They have to field their strongest team, and Sir Alex Ferguson will challenge his players to prove they are up for the fight over the rest of the season.
Make no mistake, United have been poor. Their defensive displays in particular have been a world away from the solidity of the Edwin van der Sar era.
Rio Ferdinand, sadly, looks like a player in irreversible decline. He seemed hesitant against Newcastle, unwilling to take charge.
I think his long list of injuries is slowing him down. In my last season at United I was carrying a persistent ankle problem and it does affect you.
You want to just get through the game without making any big errors, rather than seizing control of proceedings.
I'd like to see them add players in January, but you can be sure Frank Lampard won't be one of them.
Sir Alex said Chelsea won't sell him, but I don't think United want him anyway.
He's the absolute opposite of a classic Manchester United midfielder; leaden, one-paced and little more than an older Michael Carrick.
I would be very upset if United signed him, but I'm quite sure they won't.
It is now crucial that they get Tom Cleverley back as quickly as possible, and see some performances from Anderson. There is quality at Old Trafford, but not enough players are performing to their potential.
As for City - they are in an immensely strong position, and they will not miss the Africa-bound Toure brothers.
Kolo is not an automatic first-team choice, while Yaya can be replaced by the likes of Nigel De Jong or Samir Nasri - not bad stand-ins.
With that in mind, I don't know what Roberto Mancini is doing complaining about the lack of transfer funds at City.
It is a completely stupid excuse to say he cannot fill a bench when he has the deepest squad in the division.
Also, he risks alienating the owners who have spent so much money on transfers, and upsetting the fringe players who he obviously doesn't rate.
I'm not sure what he hopes to achieve by complaining - but if he wants anybody's sympathy that will be in short supply!