The Red Devils have already beaten the champions twice at the Etihad Stadium and go into this weekend's showdown on a nine-match undefeated run across all competitions to boost their hopes of securing Champions League football next term.
However, they have also lost their last three home games against their noisy neighbours and could suffer four successive derby defeats at Old Trafford for the first time since 1931.
Here, Sports Mole looks at how Ole Gunnar Solskjaer could line his side up for the contest.
Manchester United have injury doubts hanging over a couple of key players ahead of this contest, most notably captain Harry Maguire.
The world's most expensive defender missed the midweek FA Cup win over Derby County after suffering an ankle injury in training, but Solskjaer remains hopeful that he will recover in time for City's visit.
The same is true of Aaron-Wan-Bissaka and Daniel James, both of whom will undergo late fitness tests but are more likely to be available than not.
All three of those doubts could start the game if passed fit, with Maguire and Wan-Bissaka shoo-ins while James's pace on the counter-attack could appeal to Solskjaer in a game in which they are likely to surrender the lion's share of possession.
Odion Ighalo's brace on Thursday night could earn him a first Premier League start for United leading the line, which may in turn force Anthony Martial back out wide in Marcus Rashford's continued absence.
The derby comes just too soon for Paul Pogba, who is due to return to first-team training next week, but the form of Bruno Fernandes since his January arrival has helped to take the spotlight off the polarising Frenchman to a certain extent.
Many of the likely XI for this derby also featured in midweek, but David de Gea is one player who will come back into the team as he looks to bounce back from his error against Everton in the last Premier League outing.
No player has made more mistakes leading directly to goals in the Premier League since the start of last season, but Solskjaer has publicly reassured the Spaniard that he remains the first-choice goalkeeper.