The latest setbacks came during their Champions League clash against Real Madrid, where enforced substitutions weakened their performance.
Pep Guardiola was finally able to field his preferred XI - except for Rodri - for 30 minutes, but the plan was disrupted when Jack Grealish suffered an injury.
This led to a tactical reshuffle, with Phil Foden moving to the right. Manu Akanji also went off injured, forcing Rico Lewis into the game, who was then targeted by Madrid.
Nathan Ake, making his return, managed 60 minutes but was forced off, with his final action inadvertently playing Kylian Mbappe onside for the equaliser.
City's season-long injury struggles have seen players staying on the pitch despite not being fully fit, while frequent changes to the defensive line have disrupted their rhythm. Guardiola now faces a selection dilemma ahead of a crucial period.
The Premier League clash against Newcastle is followed by the second leg against Real Madrid next week.
Guardiola must carefully balance squad selection, particularly given the fitness concerns surrounding Ake, Akanji, Grealish, Jeremy Doku, and Nico Gonzalez.
Past squad rotations have backfired-Gonzalez was injured early against Leyton Orient and missed the Madrid tie.
Manchester City secured a second successive Premier League victory at home against Sunderland, Chelsea were held scoreless away to Bournemouth while Tottenham managed to beat Brentford.
Manchester City manager Pep Guardiola insists his side are moving in the right direction as they continue to evolve following an off-season of significant rebuilding.
Pep Guardiola admitted he "did not have an answer" for Manchester City's collapse in a chaotic 5-4 victory at Fulham on Tuesday night.
Tottenham snatched a dramatic 2-2 draw at St James' Park as Cristian Romero produced a 95th-minute overhead kick to rescue a point against Newcastle.
