The former Everton striker has missed the Red Devils' last two fixtures, against Sunderland and Chelsea respectively, after picking up a groin injury while on international duty with England last month.
Ashley Young and Danny Welbeck will support the forward duo from the flanks, while Ryan Giggs gets the nod over Tom Cleverley alongside Michael Carrick in central midfield. Phil Jones partners Rio Ferdinand at the back.
Sergio Aguero is only fit enough for a place on the bench for City so Carlos Tevez leads the line with David Silva, Samir Nasri and James Milner in support.
Gareth Barry is preferred to Javi Garcia alongside Yaya Toure in midfield while Vincent Kompany captains Roberto Mancini's team at centre-back.
Manchester United starting XI: De Gea; Rafael, Ferdinand, Jones, Evra; Young, Carrick, Giggs, Welbeck; Rooney, van Persie.
Subs: Lindegaard, Valencia, Hernandez, Nani, Cleverley, Kagawa, Buttner.
Manchester City starting XI: Hart; Zabaleta, Kompany, Nastasic, Clichy; Barry, Yaya Toure; Milner, Silva, Nasri; Tevez.
Subs: Pantilimon, Lescott, Dzeko, Kolarov, Garcia, Aguero, Kolo Toure.