With the Toffees' top-four challenge fading, Roberto Martinez's side find themselves in an awkward position.
A win or a draw would put bitter rivals Liverpool in pole position to land a first league title since 1990. Lose, however, and their opponents would remain favourites to lift the Premier League trophy.
Everton boast an imperious recent record over City, winning five of their last six home games and losing just once in 15 meetings—a run Reds fans will hope continues.
Everton's injury list has become as extensive as at any point this season.
Martinez will be hoping to welcome back Phil Jagielka and Sylvain Distin, as mentioned during his pre-match press conference:
Martinez confident Jagielka ready for weekend and Distin will train today and be assessed ahead of Saturday #Everton— Greg O'Keeffe (@GregOK) May 1, 2014
Both defenders sat out Everton's defeat at Southampton.
Steven Pienaar also missed that game, and Martinez revealed the South African won't return this weekend, via EvertonFC.com:
Stevie P is back with the first team.
He won’t be available this weekend, but we are trying to see if he can be involved in the final squad because it would be a great way to finish the season.
Elsewhere, Kevin Mirallas, Bryan Oviedo, Arouna Kone, Lacina Traore and Darron Gibson all remain out, while Gareth Barry is ineligible to face his parent club.
With that team news considered, here's a look at Martinez's potential starting XI:
This is one of the harder Everton XIs to predict this season.
Tim Howard will start in goal, with Seamus Coleman, Leighton Baines and John Stones making up three of his back four.
Which player not in this XI should start?
Martinez's injury reports have often magnified the positives, with absences sometimes more prolonged than first reported.
For that reason, Distin and Jagielka may again miss out, leaving Antolin Alcaraz to continue at centre-back.
Further forward, the partnership of Barry and James McCarthy will be separated for just the third time in 32 games.
With Barry unable to face his parent club, Ross Barkley and Leon Osman are Martinez's options to replace him. Given the squad's depleted look, both may end up starting a little deeper as Everton field more of a 4-3-3 shape instead of their normal 4-2-3-1.
Gerard Deulofeu's disappointing showing against Southampton should promote Aiden McGeady to the starting XI, alongside Steven Naismith and Romelu Lukaku in attack.
Keeping Sergio Aguero and Edin Dzeko quiet will be a tough task, especially if it's the job of Everton's second-choice centre-backs.
Alcaraz and Stones must show better cohesion than was the case against Southampton or the home side will be in for a long 90 minutes.
Without Barry, Everton will also lose an element of control in midfield. Martinez will be tempted to play on the counter—as they did so successfully against Manchester United—and may deploy the 4-3-3 system that's appeared in recent weeks.
Lukaku's hold-up play will be crucial in providing a platform for others to burst forward and attack from.
Prediction: Everton 1-1 Manchester City
Statistics via WhoScored.com