Paul Pogba starts for Manchester United while Sergio Aguero is among the Manchester City substitutes as the Blues look to sew up the Premier League title with victory over their derby rivals.
Pep Guardiola makes a total of four changes from the side which lost 3-0 to Liverpool in the Champions League on Wednesday, with Tuesday's return leg demanding a huge portion of his attention.
Gabriel Jesus, Kevin De Bruyne, Kyle Walker and Aymeric Laporte are replaced by Danilo, Raheem Sterling, Fabian Delph and Bernardo Silva, while Aguero is back among the match-day squad but does not start.
For United, Pogba starts in a three-man midfield alongside Nemanja Matic and the returning Ander Herrera. Eric Bailly also comes in at the heart of defence after missing the 2-0 win over Swansea City last week, with Victor Lindelof and Juan Mata both on the bench.
Pogba has been the centre of attention for the last 24 hours following Guardiola's stunning claim that the player's agent, Mino Raiola, attempted to spark a move for the Frenchman to City in January.
However, Jose Mourinho has given Pogba the start at the Etihad and the Portuguese boss will be hoping his side can delay City's title celebrations for at least a week by getting something from the 17:30 kick-off.
Manchester City: Ederson, Danilo, Kompany, Otamendi, Delph, Fernandinho, Gundogan, Bernardo, Silva, Sane, Sterling.
Subs: Bravo, Walker, Aguero, Laporte, De Bruyne, Jesus, Toure.
Manchester United: De Gea; Valencia, Smalling, Bailly, Young; Matic, Herrera, Pogba; Lingard, Lukaku, Sanchez.
Subs: J Pereira, Lindelof, Rojo, Mata, Martial, Rashford, McTominay.
