City play the Saints on Wednesday night before welcoming West Ham on Sunday, and with United travelling to Watford and Arsenal in the same period it could be an important week in this season's title race.
Pep Guardiola may rotate his squad for the two upcoming games, especially with two key players at risk of suspension ahead of the game at Old Trafford on December 10.
MAN CITY INJURIES
John Stones and Benjamin Mendy will both miss out through injury.
David Silva has been playing with a neck injury in recent weeks but is showing few, if any, outward effects.
MAN CITY SUSPENSIONS
Manchester City have no suspensions for the Southampton game but both Fernandinho and Leroy Sane are on four yellow cards, meaning another booking would rule them out of the next game.
MAN CITY POTENTIAL STARTING LINE-UP
Vincent Kompany could be rested for one of the next two games as City continue to manage his fitness. The captain returned at Leicester on November 18 but was left out of the following game against Feyenoord.
Partly thanks to injury and partly thanks to the fine form of his side, Guardiola has more or less settled upon something close to a first-choice XI in recent weeks, with only the identity of the central striker a mystery in the run up to kick-off.
Guardiola says that choosing between Sergio Aguero and Gabriel Jesus is his toughest decision at present, but has insisted that he will play both late on in games if in need of goals - as evidenced at Huddersfield on Sunday.
But with the derby on the horizon, and with a number of talented players on the bench, Guardiola could shake things up in the next two games.
Danilo and Ilkay Gundogan, for example, deputised well for Kyle Walker and David Silva in Naples at the start of November, and could easily do so again. Bernardo Silva is another option to either come into the midfield, or the front three.
There are unlikely to be sweeping changes, however, and indeed Guardiola is more likely to shuffle his pack against West Ham.
SOUTHAMPTON TEAM NEWS
Mauricio Pellegrino will have almost a full squad to choose from for Southampton's trip to the Etihad.
Matt Targett is the only player to miss out through injury, while Oriol Romeu is back from suspension and Mario Lemina returned from a month-long absence with a 12-minute cameo against Everton on Sunday.
Their only away win came against Palace, and that was during the Eagles' seven-match run without a point or a goal at the start of the campaign.
But Pellegrino is hoping for an upset against the runaway league leaders.
"Nobody is unbeatable in football and in sport," he told a press conference on Monday.
"Every single team has got problems, because [on Sunday] Huddersfield were really close to getting something.
"We have to be on the top if we want to have any chance.
"Hopefully it could be a nice day for us."
OPTA MATCH FACTS
- Manchester City are unbeaten in seven home games against Southampton in all competitions, winning six (D1), after losing three in a row prior to this run.
- Southampton have collected one point in their last six Premier League visits to the Etihad Stadium (W0 D1 L5), doing so in their 1-1 draw there last season.
- Manchester City have won 37 points from their 13 matches this season – the best-ever points total by a team at this stage of a Premier League campaign.
- On the day of this match, Manchester City will have been top of the Premier League for 74 days this season – just one day fewer than they spent top in the entirety of last season.
- Manchester City have scored 24 Premier League goals at home this season, double the number they’d scored after six home matches last season (12).
- Saints striker Charlie Austin has had a hand in eight goals in his last 11 Premier League starts (seven goals, one assist), although he hasn’t started back to back Premier League matches since December 2016.
- Only versus Aston Villa (6) has Shane Long scored more Premier League goals than versus Manchester City (4). The Irishman has found the net in each of his last two starts against the Blues in the Premier League.
TV COVERAGE & KICK-OFF TIME
Kick off is 20:00 GMT on Wednesday, November 28, though the game will not be shown live on television in the United Kingdom. It will be shown on NBC in the United States, and on various channels around the world.