The Belgian playmaker missed the 2-1 win over Fulham on Sunday due to an unspecified injury, and Pep Guardiola will have to cope without his chief creator again against the Hammers.
However, Man City are able to welcome back Nathan Ake to the matchday squad after recovering from a hamstring injury, and the defender has been thrown straight back into the starting lineup.
Guardiola has made three changes from the side that beat Fulham last time out, with the most notable change taking place between the sticks as first-choice goalkeeper Ederson has been replaced by Stefan Ortega, who is making his Premier League debut.
Ake comes in to defence at the expense of Manuel Akanji, joining captain Kyle Walker, John Stones and Ruben Dias in the back four, while Ilkay Gundogan has been replaced by Bernardo Silva who will joining Rodri in centre-midfield.
Riyad Mahrez and Jack Grealish retain their places on the flanks, while Julian Alvarez - who starred in De Bruyne's absence against Fulham - has been rewarded with another start in attack alongside Erling Braut Haaland, who is looking to break the Premier League's all-time scoring record (35 goals) for a single season.
As for West Ham, David Moyes has made four changes to the side that lost 4-3 at Crystal Palace last weekend, with captain Declan Rice, Tomas Soucek, Nayef Aguerd and Kurt Zouma all absent from the matchday squad.
Flynn Downes, Pablo Fornals, Angelo Ogbonna and Aaron Cresswell all come into the first XI, with the latter two expected to line up in a back five along with Vladimir Coufal, Thilo Kehrer and Emerson Palmieri.
Manchester City: Ortega; Walker, Stones, Dias, Ake; Rodri, Bernardo; Mahrez, Alvarez, Grealish; Haaland
Subs: Ederson, Phillips, Gundogan, Laporte, Gomez, Akanji, Perrone, Foden, Lewis
West Ham United: Fabianski; Coufal, Kehrer, Ogbonna, Cresswell, Emerson; Downes, Paqueta, Fornals; Bowen, Antonio
Subs: Areola, Johnson, Anang, Lanzini, Cornet, Ings, Benrahma
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