When: Wednesday, March 8, 18:00 GMT
How to watch: Sky Sports
Follow the game in our score centre HERE
Can City bounce back?
That loss means the gap at the top is now at 11 points with 10 games remaining and despite the slip up, it is impossible to imagine the league leaders throwing that lead away.
With the chasing pack all faltering in recent weeks, the emphasis from Guardiola will be on winning the league by the widest possible margin.
A return to form is expected from City, who it is fair to say had an off day at the Etihad - in what was their first loss since a defeat to Tottenham in November.
Last three Premier League meetings:
Southampton 0-1 Manchester City (December 19, 2020)
This game will be remembered as the one that started City's incredible winning streak way back in mid-December.
Raheem Sterling's early goal at St. Mary's helped his side move up to sixth in the Premier League table. In a week that Liverpool had beaten Crystal Palace 7-0, it seemed as though this was a must-win game for the Manchester team.
Southampton will have been disappointed to have not taken at least a point from the game, in which they had 48% possession and had plenty of chances to score.
Southampton 1-0 Manchester City (July 5, 2020)
The Saints managed their first victory against Man City since 2016, ending a barren run of seven consecutive defeats in league and cup against their opponents.
A stunning 40-yard chip from striker Che Adams, for his first Premier League goal, gave Southampton all three points.
It was a dogged defensive display by Southampton to deny substitute Kevin De Bruyne and his City team-mates. This resulted in a third consecutive away defeat for Pep Guardiola and it was the first time this had happened in his managerial career.
Man of the match Alex McCarthy was in inspired form, he made six saves as City registered 26 shots without scoring.
Manchester City 2-1 Southampton (November 2, 2019)
In another tight encounter, Sergio Aguero and Kyle Walker grabbed second half goals to win City the match.
The game came a week after Southampton's 9-0 humiliation against Leicester City, and this performance could not have been further from their dismal display in that loss.
Captain James Ward-Prowse got his side off to a flyer, when he reacted quickest to a spilled ball from Ederson to hand the Saints a half-time lead.
City failed to create any clear cut chances until the second half. Aguero's poacher-like finish levelled up the scores, before Walker's first-time finish won his team the game late on.
Head-to-head in the Premier League
Manchester City wins: 19
Southampton wins: 7
Manchester City scored: 57
Southampton scored: 34
Have Southampton stopped the rot?
Ralph Hasenhuttl's side ended a nine-game winless run by coming out comfortable 2-0 victors against the Premier League's bottom side, Sheffield United.
After a superb 2019/20 campaign, the Blades have frankly not looked like a top-flight team this season, and Southampton's display against them at the weekend confirmed that.
Southampton should have gone into the game lacking confidence, given that they had not won in the league since the start of January, but they came out all guns blazing and dominated from the first minute.
From a match that involved two teams in poor form, it is difficult to judge if Southampton are back to their best or if they were playing against a side that should already be in the Championship.
There is no doubt that they will have to be at their very best if they are to stand a chance against likely title winners, Manchester City.
A handful of recent performances against City will, however, give the Saints cause for optimism and provide them with hope. A shock 1-0 win last summer epitomised the fight Ralph Hasenhuttl's team have instilled in them. Therefore, perhaps pulling off an upset may not be out of the question.
A victory for the inconsistent side could potentially move them up a couple of places in the league and help towards securing a mid-table finish.
Scoreline prediction: Manchester City 3-1 Southampton
Even though City come into this on the back of a loss and Southampton come in off a win, that does not tell the full story.
Form-wise, Man City are still the best team in the league by some margin and you would expect them to get back to scoring ways against Southampton.
They have won seven of their last eight against the Saints and could be the perfect team to restart an unbeaten run against.
Pep Guardiola may tweak his team in order to freshen things up. Raheem Sterling and Gabriel Jesus were off the boil against Man United and with players such as Phil Foden and Sergio Aguero at their disposal, City have strength in depth in abundance.
Southampton lost their key source of goals, Danny Ings to a suspected muscle injury on Saturday, but with Che Adams leading the line there is still hope of goals for Southampton.
James Ward-Prowse always poses a threat from set pieces and he will be in a confident mood, having netted from the spot against Sheffield United.
Because of this, it would be valid to believe that both teams will score. Manchester City to win and both teams to score is available at 15/8 at Betfred and is good value from an accumulator perspective.
Raheem Sterling failed to net against Manchester United, making it 18 games without a goal against the Red Devils.
However, Southampton are a team that Sterling enjoys playing against, having an involvement in five goals in his last five games against Hasenhuttl's side.
He can rediscover his form here and is 5/4 to score anytime with multiple bettors.
Southampton striker Che Adams will get his chance to score in back-to-back games for just the second time in his Premier League career.
The former Sheffield United player scored a goal of the month contender, when smashing a shot from the edge of the box into the top corner of the net against his former club.
Adams also has history against Manchester City, scoring the only goal of the game in the home fixture last season. For this reason, we think he holds the Southampton key to a goal at the Etihad.