The Citizens are seeking to momentarily climb above Liverpool to the top of the table before the Reds play host to Burnley in a few hours' time.
De Bruyne has started the last two Premier League games for Man City following a five-month injury layoff, registering two assists, but manager Pep Guardiola is keen to manage the Belgian's minutes and has decided to name his No.17 on the substitutes' bench for the visit of Everton.
Guardiola has made a total of four changes to the side that beat Brentford 3-1 on Monday, with De Bruyne, Kyle Walker, Josko Gvardiol and Bernardo Silva all making way for John Stones, Matheus Nunes, Jeremy Doku and Manuel Akanji.
The latter returns to the starting lineup after missing the last four games with an ankle injury and will join Stones, Ruben Dias and Nathan Ake in a four-man defence protecting goalkeeper Ederson.
Rodri will be partnered by Nunes in centre-midfield, while Phil Foden - fresh from his hat-trick against Brentford - Doku and Julian Alvarez will all be providing support in attack for Erling Haaland.
Mateo Kovacic is absent from the matchday squad, so youngster Jacob Wright has stepped up to take a place on the substitutes' bench.
As for Everton, Sean Dyche - celebrating his 300th game in management - has named the same starting lineup that began the 2-2 draw with Tottenham Hotspur last weekend.
Ben Godfrey, who came off in the closing stages against Spurs with cramp, is fit to start in defence along with James Tarkowski, Jarrad Branthwaite and Vitaliy Mykolenko, while Ashley Young and Dwight McNeil will provide width on the flanks as James Garner and Idrissa Gueye links arms in midfield.
Jack Harrison, formerly on the books at Man City, is set to operate in a central role in behind central striker Dominic Calvert-Lewin.
Everton have been boosted by the return of midfielder Amadou Onana to the matchday squad, with the Belgian recovering from a muscle injury to be named among the Toffees' substitutes.
Manchester City: Ederson; Stones, Akanji, Dias, Ake; Rodri, Nunes; Foden, Alvarez, Doku; Haaland
Subs: Ortega, Walker, Grealish, De Bruyne, Bernardo, Gvardiol, Bobb, Wright, Lewis
Everton: Pickford; Godfrey, Tarkowski, Branthwaite, Mykolenko; Young, Garner, Gueye, McNeil; Harrison; Calvert-Lewin
Subs: Virginia, Patterson, Keane, Onana, Beto, Coleman, Chermiti, Hunt, Dobbin