De Bruyne has been left out of the Belgium squad ahead of the international break later this month, with head coach Domenico Tedesco revealing the playmaker is nursing a groin injury that he "has been struggling with in the last matches."
Meanwhile, Grealish has missed the last three games with a groin problem and Ederson is facing up to four weeks out with a muscle injury sustained in last weekend's 1-1 draw at Liverpool in the Premier League.
Backup goalkeeper Stefan Ortega, who has already played in three FA Cup matches this season and has kept two clean sheets, is expected to take the place of Ederson between the sticks.
Rico Lewis will push Kyle Walker for a start at right-back as Josko Gvardiol and Sergio Gomez battle with Nathan Ake for the left-back berth, while Ruben Dias could be recalled at the expense of either John Stones or Manuel Akanji to start in central defence.
Rodri was rested for Man City's 6-2 win over Luton in the fifth round, but Pep Guardiola is expected to start the Spaniard on Saturday and he could be partnered in centre-midfield by either Mateo Kovacic, Matheus Nunes or Bernardo Silva - the latter is also an option to play on the right flank.
Jeremy Doku recovered from a minor muscle complaint to feature as a second-half substitute against Liverpool and the winger is in contention to start on the left side of attack against the Magpies.
Phil Foden, Julian Alvarez and Erling Haaland all started against Liverpool and could retain their places in the final third, while Oscar Bobb - who scored a superb stoppage-time winner in a 3-2 Premier League victory at Newcastle in January - will be hoping to force his way into the first XI.
Manchester City possible starting lineup: Ortega; Walker, Dias, Ake, Gvardiol; Rodri, Kovacic; Bobb, Alvarez, Doku; Haaland