Townsend takes the place of Jordan Ayew in the attack, with Eberechi Eze and Wilfried Zaha to support Christian Benteke.
Mitchell replaces Patrick van Aanholt at left-back, with the rest of the back four unchanged: Cheikhou Kouyaté once again partners Scott Dann, with Joel Ward the final defender. Jairo Riedewald is alongside Luka Milivojevic in midfield.
Gary Cahill returns to the matchday squad and is available from the bench, with Jeffrey Schlupp, Jordan Ayew, Jean-Philippe Mateta and Michy Batshuayi all among the substitutes.
The visitors make eight changes from the side that beat Paris Saint-Germain on Wednesday, including three in attack, with the Kevin De Bruyne, Phil Foden and Riyad Mahrez dropping to the bench to be replaced by Gabriel Jesus, Sergio Agüero and Raheem Sterling.
Palace: Guaita (GK), Ward, Kouyaté, Dann, Mitchell, Riedewald, Milivojevic, Zaha, Eze, Townsend, Benteke.
Subs: Butland (GK), Van Aanholt, Ayew, Mateta, Schlupp, McCarthy, Batshuayi, Cahill, Kelly.
Man City: Ederson (GK), Aké, Sterling, Jesus, Agüero, Laporte, Rodri, Torres, Mendy, Fernandinho, Cancelo.
Subs: Steffen (GK), Walker, Dias, Gündogan, Zinchenko, De Bruyne, Silva, Mahrez, Foden.