The Citizens have confirmed that Rodri has suffered knee ligament damage and could be ruled out for the rest of the season, while both Oscar Bobb (leg fracture) and Nathan Ake (muscle) are also in the treatment room.
Kevin De Bruyne has missed Man City's last two games with a groin problem and Pep Guardiola is unsure whether the playmaker - who at the time of writing is yet to return to training - will be fit to feature this weekend.
Guardiola made a total of nine changes for Tuesday's 2-1 win over Watford in the EFL Cup and is set to recall a number of senior stars for the clash with Newcastle, including first-choice goalkeeper Ederson, Manuel Akanji, Ruben Dias and Josko Gvardiol.
Kyle Walker and Rico Lewis both played against Watford, but only one of those is set to retain his starting spot at right-back. There is, however, a scenario where Guardiola could use both, with Walker playing at right-back or right centre-back and Lewis moving into midfield in the absence of Rodri.
Mateo Kovacic is the most likely candidate to start in a deep-lying midfield role, while Matheus Nunes will also be pushing to start after scoring his first goal for the club in midweek.
Bernardo Silva, who scored twice in a 2-0 FA Cup win over Newcastle in March, is another contender to play in a central midfield role, as are Ilkay Gundogan and Phil Foden, while Savinho, Jeremy Doku and Jack Grealish are all set to battle for starts on the flanks.
Erling Haaland was absent against Watford after being granted time off to attend the funeral of close family friend Ivar Eggja in his native Norway, but the striker - who has scored 10 Premier League goals in just five games so far this term - is expected to return to the starting lineup on Saturday.
Manchester City possible starting lineup: Ederson; Akanji, Dias, Gvardiol; Lewis, Kovacic; Savinho, Bernardo, Gundogan, Doku; Haaland