The Blues raced into a three-goal lead inside the opening 20 minutes and could have run up a cricket score against the Saints.
Wesley Hoedt (own goal), Sergio Aguero, Raheem Sterling (2) and David Silva were all on the score-sheet as City maintained their 100% home record this campaign.
City took just six minutes to break Southampton down with a move that was simple and clinical.
Sergio Aguero’s persistence saw the ball fall to David Silva and his threaded pass allowed Leroy Sane to fire a low cross that Wesley Hoedt struck high into his own net.
The visitors were allowing the Blues so much space that it was no surprise when the lead was doubled just five minutes later – this time Raheem Sterling was the architect, driving towards the bye-line before crossing for Aguero to prod home from close range – his 150th Premier League goal.
Only a fine save from Alex McCarthy prevented his 151st for the Club four minutes later as the Saints defence continued to look like rabbits in the headlights – as further proved just moments later as City made the advantage three.
Sterling again raced to the bye-line before clipping a ball into the box that Sane glanced sideways and David Silva half-volleyed a powerful rising shot to effectively end the contest with 18 minutes on the clock.
It’s unlikely the Blues will ever have a more comfortable start to a top-flight game.
Yet the visitors were handed an unexpected lifeline on the half-hour mark when Ederson caught Danny Ings on a rare Saints attack and the referee awarded a spot kick that Ings himself converted.
It heralded an improved period of play from the visitors, but their reward was conceding a fourth goal in first-half added time.
Aguero chased Cedric Soares as the ball looked likely to run out of play – but the City striker out-muscled the Saints defender, then span to cross into the middle where Sterling deservedly claimed the goal his first half performance had merited.
Saints were more adventurous after the break and Ederson was forced to make two fine saves, first from Ings at point-blank range and then down to his right as a deflected corner saw the ball almost sneak in.
The Blues’ first shot in anger of the second period came when Sane smacked a sumptuous curling pile-driver onto the post just past the hour-mark.
Five minutes later and City had their fifth of the afternoon and again it was a combination of Aguero and Sterling that undid the visitors' porous defence with Argentine's pass struck home by Sterling through the keeper's legs.
The Blues completed the rout in added time after a counter-attack saw Sterling tee up Sane to fire a low drive past McCarthy to complete a miserable afternoon for Mark Hughes' side.
Man of the Match: Raheem Sterling
Two goals and two assists for City's live-wire winger who was a constant threat to the Southampton defence all afternoon.
Goal difference could be the key…
City’s ruthlessness in front of goal will be perhaps more important than ever this season in what is likely to be a nip and tuck title race.
Ultimately, the finest of margins could prove the difference for whoever is crowned champions next May.
“It’s a joy to be manager of them because they follow what we tell them.
“In training, I try to argue why we should play this way. It’s a joy and a pleasure for the staff.
“Mikel insists on many things and everyone is there to help the guys to be better.
“If at the end of our period here they are better than when we arrived, then well played to everyone.”
What it means…
City move two points clear of Liverpool at the top of the Premier League, with Chelsea looking to move second with a victory in today’s later kick-off against Crystal Palace.
City return to Champions League action on Wednesday evening against Shakhtar Donetsk, looking for a third straight Group F win.
Then all eyes will be on next Sunday’s Manchester derby, with United the visitors at the Etihad.