The Citizens had their ninth top-flight win of the season wrapped up with less than a quarter of the game played, finding themselves three goals to the good through a Wesley Hoedt own goal and strikes from Sergio Aguero and David Silva.
Danny Ings pulled one back for Southampton from the penalty spot, but Raheem Sterling added his name to the scoresheet with a couple of goals of his own either side of half time, before Leroy Sane rounded off the scoring in added time.
City, who required a goal in the 96th and 94th minute to earn all three points in last season's games against Southampton, have now scored five or more goals in a league game under Pep Guardiola on 15 occasions.
Southampton headed into the match winless in six league matches and without a goal in five of them, and what was always going to be a difficult task was made even tougher when conceding six minutes in.
Sane, returning to the side in place of Riyad Mahrez in City's only change from the 1-0 win at Tottenham Hotspur on Monday, fired in a low cross which Hoedt could only divert into the roof of his own net from under the crossbar.
One goal became two six minutes later as the division's highest scorers went through the gears, with Aguero tapping in at the back post for his landmark 150th Premier League goal following some good work from Sterling.
Sterling was then denied by a smart Alex McCarthy stop, but the Englishman was again involved a couple of minutes later as his chipped delivery was smashed into the back of the net by Silva for City's third of the match.
Southampton, who had kept back-to-back clean sheets prior to today, were given a route back into the match half an hour in as Ederson raced off his line and wiped out Liverpool loanee Ings, leaving referee Lee Mason with no choice but to point to the penalty spot.
Ings stepped up and rolled the ball to Ederson's left - the first penalty that the Brazilian has conceded in the English top flight, having saved the last two, ending his hopes of keeping a club-record seventh clean sheet in a row.
City restored their three-goal advantage before the interval, however, thanks to Sterling's simple finish past McCarthy after Aguero kept the ball in play and squared it to his teammate, though the Englishman required a couple of bites of the cherry after miscuing his initial shot.
The hosts were guilty of taking their foot off the gas in the second half, and it could have been game on again as James Ward-Prowse and Ings both had attempts kept out by Ederson - the latter nodding a corner downward to force the Brazilian into a fine stop down low.
A fifth home goal would arrive with around a quarter of the game to play, however, as Sterling fired the ball across McCarthy from an angle once teed up by Aguero, shortly after Sane had curled a shot against the frame of the goal.
Shane Long should have pulled one back for the south coast side late on, only to shoot wide from eight yards, and it was then left to Sane to stroke the ball out of McCarthy's reach from the edge of the area to cap another impressive City display.
MANCHESTER CITY (4-3-3): Ederson; Walker, Stones (Kompany 68'), Laporte, Mendy; Bernardo, Fernandinho (Delph 79'), D.Silva (Foden 72'); Sane, Aguero, Sterling
SOUTHAMPTON (4-4-2): McCarthy; Soares, Stephens, Hoedt, Bertrand; Redmond (Elyounoussi 74'), Ward-Prowse (Obafemi 73'), Hojbjerg, Lemina; Long, Ings (Armstrong 82')