Manuel Pellegrini's men sit in third place with 77 points, three behind leaders Liverpool and one adrift of Chelsea, but with an extra match to play and a superior goal difference, three successive wins should secure the trophy.
Their final two games are at home to Aston Villa and West Ham United, both woefully out of form, and the 2011-12 champions would back themselves strongly to take six points against sides in the bottom half of the table.
The trip to Goodison Park on Saturday(1630 GMT) looks less straightforward, however, as Everton, who have lost two of their past three matches, still have an outside chance of finishing fourth for the first time since 2005.
City fought back from a goal down to win 3-1 when the sides last met, and Argentine right back Pablo Zabaleta said they could not waste the opportunity.
"The next game is Everton away and we know it is going to be tough. Everton away has been difficult for us. They are playing for fourth place so nothing is going to be easy and we need to show character, personality. We have got a big chance.
"We said before Crystal Palace we need Liverpool to drop some points. They have but nothing is settled. We need to continue working hard like we have done during the whole season and hopefully we can win the next three games.
"Now everything is in our hands again. We have three games to play, and everything is in our hands again. We know we must win those games if we are to win the title again but it's going to be very difficult."
Pellegrini may risk attacking midfielder David Silva, who missed the win over Crystal Palace with an ankle injury.
Everton find themselves in the awkward position of being able to hand local rivals Liverpool a boost in their challenge for the title should they win, and while the players are unlikely to fight for anything other than victory, some fans may not be too unhappy if they lose to City.
Defeat by Southampton was a major blow to their hopes of qualifying for the Champions League and fourth-placed Arsenal need a home win over West Bromwich Albion on Sunday (1230) to secure a place in Europe's elite club competition for the 17th consecutive season.
Liverpool travel to Crystal Palace on Monday (1900) with plenty of time to digest whether or not Everton did them a favour, but regardless of where they are placed in the title race, manager Brendan Rodgers told his players to enjoy their unexpected rise to Premier League heavyweights.
"We want to win, of course, and we are in a brilliant position," Rodgers, whose side are guaranteed a top-three finish, said.
"But we must enjoy it - this is brilliant, the supporters are loving it, we are showing the real scale of the club and what these players are about, and that is just as important."
The other team in the title race are second-placed Chelsea, despite manager Jose Mourinho's claims to the contrary, and they could take advantage if either Liverpool or Manchester City slip up in the season's final stretch.
They are at home on Sunday to struggling Norwich City, who dropped into the relegation zone following defeat by Manchester United, and will be looking to bounce back after losing to Atletico Madrid in their Champions League semi-final on Wednesday.
Manchester United will be out to prove the 4-0 defeat of Norwich in Ryan Giggs' first match in charge since replacing David Moyes was more than just a one-off, but will come up against a rejuvenated Sunderland side on Saturday fighting for their Premier League life (1400).
The Black Cats moved out of the relegation zone on goal difference after the weekend's victory over Cardiff, having previously beaten Chelsea away and drawn at Manchester City, and will be looking for more goals from Connor Wickham, who has netted five times in three matches.
"In the box Connor is a big presence and he keeps defenders busy," fellow striker Fabio Borini said.
"He scored from two corners on Sunday and that's what we need from him. He's a big lad who is physically massive and gives us that extra presence in the box."
Aston Villa will look to arrest an alarming slide that has seen them pick up one point from six matches to leave them three points outside the relegation zone when they host Hull City on Saturday (1400), while West Ham will be aiming to beat Tottenham Hotspur for the third time this season when they meet at Upton Park (1145).
Saturday's other matches see Newcastle United host bottom club Cardiff City, Fulham travel to Stoke City and Swansea City play Southampton (all 1400).