Saints dominated the game from start to finish but had a series of defensive errors from City, including a Gareth Barry own goal, to thank for the win, their first under new manager Mauricio Pochettino.
Jason Puncheon got Southampton off to a flying start on the south coast when he followed up Jay Rodriguez's rebounded shot to slide the ball into an empty net after seven minutes.
A quarter of an hour later Rickie Lambert's shot was spilled by Joe Hart into the path of Steven Davis, allowing the midfielder to double Saints' lead from close range.
Edin Dzeko halved the deficit before half-time and put Manchester City back in the game against a Southampton side who have dropped more points from winning positions than any other Premier League side this season.
But three minutes into the second half Lambert's cross rolled through the box and Barry passed the ball into his own net, a horrendous error from the England midfielder who will want to put this performance quickly behind him.
City never looked like getting back into the game and the same may now be said of their campaign. The current title holders are nine points behind Manchester United who have a game in hand against Everton tomorrow afternoon, while at the other end of the table Southampton move six points clear of the bottom three.