City have the second leg of their Champions League quarter-final tie with Liverpool on Tuesday and trail 3-0 after the opening game at Anfield.
Only six Premier League games remain after the derby and with City having a 16 point lead at the top of the table, Guardiola chose to leave Belgian De Bruyne on the bench along with Kyle Walker, strikers Sergio Aguero and Gabriel Jesus and French defender Aymeric Laporte.
Guardiola's line-up does not include a recognised central striker and there are starts for midfielder Bernardo Silva, Fabian Delph and Danilo.
United manager Jose Mourinho left forwards Marcus Rashford and Anthony Martial on the bench opting for Alexis Sanchez, Jesse Lingard and Romelu Lukaku in a three-pronged attack.
Ander Herrera features in midfield alongside Nemanja Matic and Paul Pogba.
(Reporting by Simon Evans; Editing by Christian Radnedge)
