Leroy Sane joins Aguero and Jesus in the frontline in what is expected to be a 4-3-3 formation against the Ukrainian champions, with Kevin De Bruyne, Fernandinho - starting against his former side - and captain David Silva operating in the midfield.
Fabian Delph earns a recall at left-back after Benjamin Mendy was forced off against the Eagles with a knee injury, while Kyle Walker, John Stones and Nicolas Otamendi all keep their places and Ederson stays put in goal.
Among the options on the bench for Guardiola is Yaya Toure, who has made just one appearance in the EFL Cup for the Citizens this term.
Meanwhile, Shakhtar boss Paulo Fonseca has made two changes following the 4-2 victory at Zirka Kropyvnytskyi on Saturday as he looks to build on the side's impressive win over Napoli earlier in the month.
Bernard replaces Alan Patrick as partner for Taras Stepanenko in front of an unchanged back four of Bohdan Butko, Ivan Ordets, Yaroslav Rakitskiy and Ismaily. Andriy Pyatov is back between the sticks.
Manchester City: Ederson; Walker, Stones, Otamendi, Delph; D Silva, Fernandinho, De Bruyne; Sane, Aguero, G Jesus
Subs: Bravo, Danilo, Sterling, Gundogan, Mangala, Bernardo, Yaya Toure
Shakhtar Donetsk: Pyatov; Butko, Ordets, Rakitskiy, Ismaily; Bernard, Stepanenko; Marlos, Taison, Fred; Ferreyra
Subs: Shevchenko, Khocholava, Azevedo, Dentinho, Patrick, Petryak, Kovalenko
Keep up with all of the action from the Etihad tonight with Sports Mole's live text commentary here.