Costel Pantilimon comes in for the England international, while Martin Demichelis continues to deputise alongside Matija Nastasic at the back and Gael Clichy is preferred to Aleksandar Kolarov at left-back.
Elsewhere, James Milner is replaced by Jesus Navas on the right side of midfield.
Tottenham boss Andre Villas-Boas make six changes, as Lamela makes his first Premier League start, with Andros Townsend dropping down to the the bench while Hugo Lloris returns in goal.
Emmanuel Adebayor is also a substitute against his former side, on a strong bench which also includes Mousa Dembele, Jermain Defoe and Gylfi Sigurdsson.
Manchester City (4-2-3-1): Pantilimon; Zabaleta, Demichelis, Nastasic, Clichy; Fernandinho; Navas, Yaya Toure, Nasri; Negredo, Aguero.
Subs: Hart, Lescott, Richards, Guidetti, Garcia, Milner, Dzeko.
Tottenham (4-2-3-1): Lloris; Walker, Dawson, Kaboul, Vertonghen; Paulinho, Sandro; Lennon, Holtby, Lamela; Soldado.
Subs: Friedel, Chiriches, Dembele, Townsend, Sigurdsson, Adebayor, Defoe.