Manuel Pellegrinis 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 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.
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 Europes elite club competition for the 17th consecutive season.
Liverpool travel to Crystal Palace on Monday 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. We want to win, of course, and we are in a brilliant position, Rodgers, whose side are guaranteed a top-three finish, said Brendan Rodgers. 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 Mourinhos claims to the contrary, and they could take advantage if either Liverpool or Manchester City slip up in the final stretch. They are at home on Sunday to struggling Norwich City, who dropped into the relegation zone following defeat by Manchester United.
RVP set to return
Wayne Rooney is doubtful for Manchester United's Premier League game against Sunderland on Saturday but Dutch striker Robin van Persie could return, interim manager Ryan Giggs said on Friday. The news comes at the back of several reports from the British media saying Van Persie may be joined at United by his Dutch coach Louis van Gaal. The announcement is expected to be made next week.
Rooney is one of several players who have picked up a bug this week. Wayne has also got a tight groin so obviously with the bug you have to be careful because his immune system is down, Giggs said. There was better news of Van Persie, whose hamstring injury has kept him out for more than a month since scoring a hat-trick in the Champions League victory over Olympiakos.
United will be out to prove the 4-0 defeat of Norwich in 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. The Black Cats moved out of the relegation zone on goal difference after the 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.
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 on Saturday, while West Ham will be aiming to beat Tottenham for the third time this season when they meet at Upton Park.