The Red Devils have not won back-to-back derbies since 2010 and come into this match still looking for their first win and first goal of the year.
United were the last team to beat Man City in this competition, though, with Tuesday's visitors having lifted the trophy in both seasons since that October 2016 defeat.
Here, Sports Mole looks at how Ole Gunnar Solskjaer could line his side up for the crunch match.
Out: Paul Pogba (ankle), Scott McTominay (knee), Axel Tuanzebe (hamstring), Marcos Rojo (muscle), Eric Bailly (knee), Timothy Fosu-Mensah (knee)
Doubtful: Anthony Martial (illness), Jesse Lingard (illness), Luke Shaw (illness)
Solskjaer's options have been further depleted by an illness running through the squad, with Anthony Martial, Jesse Lingard and Luke Shaw all doubts for this match as a result.
Solskjaer is expected to name most of his key men in the starting XI, though, particularly given the importance of building an advantage in the home first leg.
However, Paul Pogba and Scott McTominay remain sidelined through injury, while Axel Tuanzebe, Marcos Rojo, Eric Bailly and Timothy Fosu-Mensah are not due to return until later this month.