Newcastle hand a first start to 17-year-old midfielder Lewis Miley, who has one 14-minute appearance in the Premier League to his name from last season.
He is one of 10 changes, that sees only goalkeeper Nick Pope survive from the XI that hammered Sheffield United 8-0 on Sunday.
Jamal Lascelles and Paul Dummett come in at the heart of defence, summer signings Lewis Hall and Tino Livramento get a chance to stake a claim, while Sandro Tonali is the experienced head in midfield.
The bench includes plenty of first-team talent – Kieran Trippier, Bruno Guimaraes and Miguel Almiron included – should things take a turn for the worse.
Newcastle team news – 10 changes
Newcastle: Pope, Livramento, Lascelles, Dummett, Targett, Hall, Miley, Tonali, Murphy, Joelinton, Isak.
Subs: Karius, Trippier, Schar, Gordon, Ritchie, Manquillo, Almiron, Anderson, Guimaraes.
Man City team news – Eight changes
Man City: Ortega, Lewis, Akanji, Ake, Gvardiol, Gomez, Phillips, Kovacic, Bobb, Grealish, Alvarez.
Subs: Ederson, Carson, Walker, Dias, Haaland, Doku, Nunes, Foden, Hamilton.