Goals from Yaya Toure, Frank Lampard and Gael Clichy gave Manuel Pellegrini's men a resounding victory over Ronald Koeman's side at St. Mary's on Sunday.
The Ivory Coast international slammed home a fine drive to give City a second-half lead before Lampard and Clichy wrapped up all three points in the final 10 minutes, despite Eliaquim Mangala’s sending off.
However, City was left sweating over a potential injury problem suffered by Vincent Kompany, with the club captain limping off in the final minutes.
Southampton went into Sunday's game flying high after a stunning start to the season, but was given a reality check in a comprehensive performance from Manuel Pellegrini's side.
In-form striker Sergio Aguero was denied what appeared to be a clear penalty early on when he was fouled in the box by Jose Fonte, only for referee Mike Jones to caution him for simulation — much to the Argentinian's bemusement.
Southampton almost caught City on the counter in the 21st minute but an unmarked Graziano Pelle failed to get a significant touch on Morgan Schneiderlin’s cross, before Joe Hart saved well on Steven Davis — making his return from a hamstring injury — on the rebound.
A sweeping City move then ended with Stevan Jovetic, one of four changes from the midweek win over Bayern Munich, squeezing a shot past Fraser Forster shortly before the break, but Toby Alderweireld did well to get back and clear off the line.
Koeman was forced into a change at halftime, with Maya Yoshida replacing Schneiderlin due to a thigh injury, but Southampton began the second period on the front foot, with long-range strikes from Alderweireld and Dusan Tadic far away.
However, City went in front six minutes after the restart when Toure was teed up by Aguero on the edge of the area, and his powerful low shot took a slight deflection off Alderweireld and ended up in the bottom corner.
Koeman attempted to inject more of an attacking threat as Shane Long came on for Sadio Mane in the 67th minute, but it was City that almost struck again soon after when captain Vincent Kompany — who was forced off late on with an apparent injury — flicked on a corner and Aguero fired over from close range on the volley.
Long's pace came into play soon after, though, as he was brought down by Mangala while racing toward Hart's goal. The Frenchman, who has endured a tough start to life in the Premier League, received a second yellow to hand Southampton an apparent route back into the game.
But as the hosts chased the game, Aguero was again involved in a fine City break before substitute Lampard raced onto James Milner's pass and fired past Forster from 20 yards.
The Southampton goalkeeper did well to deny Aguero as he raced clean through on another devastating counter, but the forward turned provider once more in the closing stages to set up Clichy for a third, though Kompany's late injury gave City something of a headache ahead of its clash with Sunderland on Wednesday.