The striker, who was left out of the victory over Sunderland at the weekend, is absent due to a groin strain while John Terry is dropped from the Blues' starting XI
Netherlands international Van Persie, who started Saturday's 1-0 victory over Sunderland in the Premier League, is named on the bench while Rooney, who missed the game at the Stadium of Light, is left out of the matchday squad completely having picked up a groin injury on England duty.
Sir Alex Ferguson instead opts to start with both Javier Hernandez and Danny Welbeck, while Nani is picked on the left flank and Rio Ferdinand and Patrice Evra return to the back four.
For Chelsea, Rafael Benitez has rung the changes following Saturday's defeat to Southampton, with Mata recalled to the side while Demba Ba replaces Fernando Torres in attack.
John Terry, who started and scored at St. Mary's at the weekend, is dropped as Branislav Ivanovic and David Luiz form the partnership in the centre of the Blues' defence.
Chelsea: Cech; Azpilicueta, Ivanovic, Luiz, Cole; Mikel, Ramires; Hazard, Mata, Oscar; Ba.
Subs: Turnbull, Terry, Benayoun, Bertrand, Moses, Lampard, Torres
Manchester United: De Gea; Jones, Smalling, Ferdinand, Evra; Valencia, Carrick, Cleverley, Nani; Hernandez, Welbeck.
Subs: Lindegaard, Giggs, Young, Van Persie, Powell, Kagawa, Vermijl.