The hosts also enjoyed a comfortable win of their own against Watford last time out, and Ralph Hasenhuttl's side have all but guaranteed their Premier League status for another season.
Southampton managed to hit the all-important 40-point mark following last weekend's victory at Watford, and the Saints now have a comfortable margin of 13 points separating them from the relegation zone.
With only six games left to play, it seems inconceivable that Hasenhuttl's men would drop enough points to become embroiled in a relegation dogfight, although their clash with the former champions this weekend is followed up by further testing fixtures against Everton and Manchester United.
Nevertheless, Saints fans are sure to feel confident about their side's fortunes following the win at Vicarage Road, with the prolific Danny Ings netting twice to take his league tally to 18 goals for the season, just one behind current top scorers Jamie Vardy and Pierre-Emerick Aubameyang.
Hasenhuttl's men will now look to win at St Mary's for the first time since the restart, with the Saints losing their first fixture back on home soil to Arsenal, although they have taken points off both Tottenham Hotspur and Manchester United on familiar territory this season.
Southampton are in no danger of dropping any further down the table this weekend, with 15th-placed Brighton & Hove Albion seven points adrift of the Saints, but Hasenhuttl could witness his side jump two places to 12th with a shock victory if Crystal Palace and Newcastle United both suffer defeat.
Despite having already relinquished their title to Liverpool before welcoming the champions to the Etihad, Manchester City did not rest on their laurels as they dismantled Jurgen Klopp's side with ease on Thursday evening.
The Reds barely had any time to bask in adulation following their guard of honour as Kevin De Bruyne, Raheem Sterling, Phil Foden and an Alex Oxlade-Chamberlain own goal condemned Liverpool to just their second league defeat of the season, with City certainly keen to make a statement of intent ahead of the 2020-21 campaign.
Pep Guardiola's side have almost nothing to play for in the Premier League having all but confirmed their runners-up spot, and the City manager will no doubt look to prioritise the FA Cup and Champions League as his side look to secure a domestic and European treble for the 2019-20 campaign.
All of City's remaining fixtures in the English top flight are against sides in the bottom half of the table, but if there is anything that we know above all else about Guardiola, it is that he will be demanding 100% effort from his players no matter the quality of the opposition facing them.
However, the former champions have actually suffered losses in three of their last four matches away from home, although those defeats were against Champions League-chasing sides in Tottenham Hotspur, Manchester United and Chelsea.
Guardiola's men were indebted to a late Kyle Walker winner in November as they recorded a 2-1 victory over the Saints at the Etihad, with Sergio Aguero initially levelling the scores after James Ward-Prowse's opener for Southampton.
Southampton Premier League form:
Manchester City Premier League form: WLWWLW
Manchester City form (all competitions): LWWLWW
Southampton's former captain Pierre-Emile Hojbjerg, who continues to be linked with a move away from the South Coast club, is unlikely to feature with an ankle problem.
Sofiane Boufal is also struggling with a thigh complaint but may be fit enough to make the bench, while Moussa Djenepo and Jack Stephens are back in the fold having served their respective suspensions.
City are also welcoming a player back from suspension themselves, with Fernandinho in line to return to the defence after sitting out the last two matches following his red card against Chelsea.
Guardiola has become renowned for his infamous rotation during his time at City, but the Spaniard may be reluctant to make too many changes to the side that comfortably dispatched Liverpool in midweek.
Southampton possible starting lineup:
McCarthy; Walker-Peters, Bednarek, Stephens, Bertrand; Armstrong, Ward-Prowse, Romeu, Redmond; Ings, Long
Manchester City possible starting lineup:
Ederson; Cancelo, Laporte, Fernandinho, Zinchenko; Rodri, De Bruyne, Foden; Mahrez, Jesus, Sterling
We say: Southampton 1-4 Manchester City
Both sides have very little to lose in this fixture and that should make for an exciting spectacle at St Mary's, but the attacking prowess of Man City is simply too good to ignore and we are going for a straightforward victory for Guardiola's men this Sunday.