Champions City go into the blockbuster match-up a point ahead of the Reds, knowing defeat could see them drop as low as fifth if results go against them.
But they could go into the top of the table match without as many as five first team players to add to Kevin De Bruyne, John Stones and Sergio Gomez's long-term injuries.
One of those stars who could be absent is goal machine Erling Haaland, who has already banged in 17 times this season in all competitions.
The 23-year-old picked up an ankle knock while on international duty for Norway, resulting in him missing Sunday's 3-3 draw against Scotland.
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Commenting on his injury, Norway boss Stale Solbakken said: "It's the movement in his foot that is the problem but it's not a serious injury.
"Had it been a final, I don't know [if he would have still risked playing]. All parties agree it is probably a little too soon but it is not a career-threatening injury."
City goalkeeper Ederson has also picked up a minor injury, having hurt his ankle in the final stages of the 4-4 draw against Chelsea, resulting in him pulling out of Brazil's squad.
Brazil's team doctor Rodrigo Lasmar remarked: "After the game, the player got in touch, as did Manchester City's medical department.
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"'He suffered a foot injury in the final minutes and was able to continue the match, but the pain became intense. The foot became swollen, difficult to walk."
Along with Haaland and Ederson, Mateo Kovacic, Nathan Ake and Matheus Nunes all have had setbacks of their own.
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Should all five players be ruled out, Guardiola will have to tinker up his team in his quest to claim the three points.
Stefan Ortega would come in for Ederson between the sticks, with the German establishing himself as one of the best backups in the league since joining last year.
Just like in the draw away at Stamford Bridge, Guardiola could opt to play in a 3-2-4-1 formation.
With Ake potentially out, a back three could consist of Kyle Walker, Ruben Dias and Josko Gvardiol.
And with Nunes and Kovacic major doubts, natural defender Manuel Akanji could once again play as a defensive midfielder alongside Rodri.
Phil Foden and Jeremy Doku could then be deployed on the wings, with Jack Grealish recalled to the starting XI to play next to Bernardo Silva in advanced central role.
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Should Haaland miss his first top-flight game this term, World Cup winner Julian Alvarez would then be tasked with leading the line.
Alvarez has been in great form playing behind Haaland this term - chipping in with seven goals and five assists in 18 games in all competitions.