Town's home troubles continued with a second successive Championship defeat as Southampton left Portman Road with all three points.
Goals from Keith Andrews and Jay Emmanuel-Thomas threatened a comeback after Blues went in at the break three down but a brace from Adam Lallana added to first-half goals from Rickie Lambert (2) and David Connolly sealed a third successive League win for Saints.
Town made two changes to the side that lost to Hull with Jason Scotland and Andrews starting in place of Emmanuel-Thomas and Lee Martin.
Saints started the game brightly and midfielder Lallana flashed a shot just past 'keeper David Stockdale's post in the second minute.
The visitors then took the lead after just four minutes with Lambert coolly finishing past Stockdale after a smart one-two with strike partner Connolly.
Things got worse for Town in the 11th minute as Lambert got his - and Southampton's second goal of the game, after being fed by Lallana, the striker calmly finishing past Stockdale.
With some clever forward running from the visitors, Guly Do Prado managed to find some space in the box but his shot was just wide of Stockdale's post after more good work from Connolly.
This seemed to spring Town into action and Blues almost pulled a goal back in the 19th minute thorugh Lee Bowyer, but he was thwarted by a fine stop from former Town 'keeper Kelvin Davis in the Saints' goal.
A coming together between Michael Chopra and Dan Harding in the area drew shouts for a penalty from the home crowd but referee Jonathan Moss waved away the protests.
Town almost provided a goal of real quality in the 23rd minute, after some flowing one touch football saw Andrews head across the box to Aaron Cresswell but the left-back failed to hit the target from ten yards.
A quick counter attack from Town on the half hour mark saw Scotland outpace defender Jose Fonte but his fierce shot failed to test Davis in the Saints goal and flew wide.
However it was the visitors who scored next and extended their lead. Good work on the edge of the box from Lallana saw him slip in Do Prado and after he rounded Stockdale and laid the ball back, Connolly was on hand to smash the ball home.
Paul Jewell introduced Emmanuel-Thomas and Martin for the second-half in place of Mark Kennedy and Scotland to try and engineer a response from his Town players.
That is exactly what he got as in the 56th minute Town pulled a goal back through Andrews, who smashed home from just outside the area after Michael Chopra's initial shot had cannoned off the bar.
The visitors responded well though as Lallana danced his way through the Town defence just a minute later and placed a shot past Stockdale that looked destined for the corner but for a fantastic clearance off the line from Cresswell.
Yet it was Town who were next on the scoresheet just a minute after the hour mark with substitute Emmanuel-Thomas bundling the ball home after a goalmouth scramble in the Saints' box.
Town were piling the pressure on Saints and with the Portman Road crowd right behind the side Blues went in search of an equaliser which almost came courtesy of Grant Leadbitter, but the skipper couldn't quite get on the end of Cresswell's teasing cross.
Emmanuel-Thomas looked threatening and he came close to doubling his account in the 72nd minute when he forced a smart save out of Davis from a tight angle.
However it was Saints who scored the next goal and it was a goal of true quality, with Adam Lallana finishing off a superb passing move with a smart finish after being fed by substitute Morgan Schneiderlin.
Town continued to press in search of getting back into the game and went close through Martin after being fed by Emmanuel-Thomas but his deflected shot was eventually gathered by Davis.
Southampton put further misery upon Town as Lallana raced clear before finishing past Stockdale for his second and the visitors' fifth in added on time to maintain their 100 per cent record this season.
Town are next in action on Saturday away at Peterborough and will be looking to get back to winning ways in front of the Sky cameras at London Road, kick-off 5.20pm.
Town: Stockdale, Edwards, Smith, Delaney, Cresswell, Leadbitter, Kennedy (Martin 46), Andrews, Bowyer, Chopra, Scotland (Emmanuel-Thomas 46). Subs not used: Lee-Barrett, Ainsley, Ellington. Booked: Delaney, Chopra
Saints: Davis, Richardson, Harding, Fonte, Seaborne, Cork, Hammond, Lallana (De Ridder 90), Do Prado (Schneiderlin 71), Lambert, Connolly (Fox 77). Subs not used: Bialkowski, Martin. Booked: Richardson