With Manchester United taking on Liverpool in Saturday's early kick-off, City will go into their game knowing they could potentially finish the day three points clear of second-placed United or ten clear of Liverpool.
Meanwhile, mid-table Stoke are hoping to spring a surprise and move a little further from the relegation zone, with three points currently separating them from the bottom three.
The hosts could be boosted by the return to match fitness of Sergio Agüero, who suffered a broken rib in a car crash in Amsterdam before the international break.
Pep Guardiola has confirmed that the Argentine has been back to full fitness and with a Champions League clash with Napoli looming, could use this fixture to test Agüero's readiness for action.
Fabian Delph could miss out due to a hamstring issue, which would likely see Danilo come in for the injured Benjamin Mendy at left-back, though Delph has trained.
A concussion suffered on international duty means that Stoke will be without Welsh midfielder Joe Allen, while Ryan Shawcross and Bruno Martins Indi will be absent from the Potters' defence.
Guardiola offers injury update
Fresh from winning September's Manager of the Month award, Guardiola confirmed that while Agüero could feature in this game, club captain Vincent Kompany is still out of contention.
"He is not 100% but he recovered quite well," he said of Agüero in his pre-match press conference. “We will see. We are happy he is back in training.”
Should the striker feature, one goal would be enough to draw level with Eric Brook's club-record haul of 177 Manchester City goals.
“He [Kompany] is much, much better but still injured,” the Spaniard added.
“Hopefully, it is the last part. It depends on him when he will come back. He will notify us.”
Hughes ready for uphill challenge
City are averaging more than three goals per league game so far this season, and Stoke boss Mark Hughes has admitted that his side have a task on their hands to keep their rampant frontline quiet.
“They have individuals who can turn the game in an instant," he told Stoke City+.
"They have any number of those players too, so we have to accept and understand that and try to stop them from having too many opportunities, or sights at goal.”
However, the former Manchester United man was keen to emphasise his belief in his own players to pull off what would be one of the shock results of the season so far.
“Nobody expects us to win," he went on, "but that means nothing - it is all about what we can do on the day, so let's get out there and see what we can do, because we have players that can turn the game with a piece of individual brilliance too.”
Despite the odds being against the away side, Stoke have fared reasonably well in recent clashes between the two sides with two wins from the last six meetings.
The Potters last won in this fixture in December 2015 thanks to a Marko Arnautović brace, while a goalless draw at the tail-end of last season frustrated fans at the Etihad Stadium as City's season slumped.
Should Stoke take three points and results elsewhere go their way, the away side could finish the day in the top half.