For City, the Premier League title is at stake with Pep Guardiola's men needing to win their remaining four matches to be sure of becoming the first side since United a decade ago to retain the title.
Those days of dominance are long gone for the Red Devils with just a place in the top four and Champions League qualification their target.
However, United also have to restore some sense of pride after a 4-0 thrashing at Everton on Sunday.
Defeat at Goodison Park was United's sixth in eighth games, a run that has seen them crash out of the Champions League and FA Cup, as well as slip back down to sixth in the Premier League.
But with Tottenham, Arsenal and Chelsea also faltering, they remain just three points off the top four.
The momentum and feel good factor built up by Ole Gunnar Solskjaer's first few months in charge has gone.
Now the Norwegian, only hired on a permanent basis last month, has to show he has the ability to arrest the slump even before a major restructure of his squad takes place in the summer.
Solskjaer questioned the work rate and desire of some of his players on Sunday, making it clear that big changes are needed.
However, he is clinging to the hope that those he currently has to call on will be shocked into a short-term response.
"Against City at Old Trafford on Wednesday, that's the biggest incentive we can have," said Solskjaer after the Everton embarrassment.
"Old Trafford at home, in front of our fantastic fans, they were unbelievable again and they never ever moaned at our players, which they could have, but they've been supportive and I'm sure they will be on Wednesday night."
Yet, there is a dilemma even for United fans keen to halt City's rise.
Should City fail to win at Old Trafford, Liverpool -- historically United's fiercest rivals -- will be just three games away from a first league title in 29 years.
Liverpool have already set their highest ever points tally in the Premier League era of 88 to lead City by two points.
However, Guardiola's men have a game in hand and should they move top once more with a win on Wednesday, would just need to see off Burnley, Leicester and Brighton to guarantee the title.
"With this Liverpool side, our side we know if we lose what happens," warned Guardiola.
City's quest for a quadruple of trophies fell short by the finest of margins as they lost on away goals to Tottenham in the quarter-finals of the Champions League last week.
However, they can still claim an unprecedented domestic treble by winning the league and FA Cup over the next month to go with their League Cup win in February.
"I love my team being there," added Guardiola.
"I am not going to criticise them because we are out (of the Champions League). I see every day what we have done over the past two seasons, they show me character every three days.
"I have good players, but they have to do it. And when people expect them to do it, it's harder to do it. That's why we push them but they respond really well. I love my team."
City gained a small measure of revenge on Spurs with a 1-0 league win on Saturday, but victory came at a cost with Kevin de Bruyne unlikely to play again this season due to a hamstring injury.