The former Atletico Madrid striker is currently is coronavirus isolation after coming into contact with someone who has the virus. Though it is unconfirmed whether or not he has been infected himself, he will have to hand in a negative test before the game on Wednesday if he is eligible to feature.
He could still do that, but the more likely scenario will be him sitting out another game, which opens up the door for Gabriel Jesus to start up top again.
Just behind the Brazilian, Guardiola might make an alteration from the weekend, though, with Riyad Mahrez potentially coming in to replace Bernardo Silva, who didn't impress to much on the right wing.
Raheem Sterling scored a fantastic free-kick versus Palace, and should retain his place on the left.
Fernandinho was one of City's top performers at the weekend, earning a 8.4 FC Rating, but will likely drop to the bench again, with Phil Foden potentially coming into the starting XI after impressing recently.
Should that happen, De Bruyne could be asked to play in the deep-lying midfield two which will allow Foden to play further forward.
If not Foden, then another possibility could be Rodri coming in.
The best player of the Premier League weekend was John Stones, who recorded a perfect 10 FC Rating for his performance against Palace. As well as scoring a goal, he completed 112/117 passes, solidifying his status as a guaranteed starter for City at the moment.
Ruben Dias will likely partner him again, with Aymeric Laporte not yet fully fit after recovering from a hamstring injury.
Nathan Ake is back in contention, but we'll likely see him in action in the FA Cup at the weekend.
Oleksandr Zinchenko and Kyle Walker should retain their places from the weekend, though Joao Cancelo is pushing for a start on both flanks.