Leif Davis gave the Blues the lead but Southampton but Che Adams and Adam Armstrong hit back for the Saints to give the visitors a 2-1 half-time lead at Portman Road.
Town made two changes from the team which won 1-0 at Blackburn Rovers on Good Friday with Cameron Burgess and Kayden Jackson coming into the XI.
Burgess replaced George Edmundson at the centre of the defence having come on as a sub late on at Ewood Park having been in Australia on international duty until late last week.
Jackson took over from Nathan Broadhead, who like Edmundson was on the bench, and was on the right with Omari Hutchinson switching to a narrow left-sided role.
Southampton included three former Blues, midfielder Flynn Downes, making his first competitive return to Portman Road, right-back James Bree and winger Ryan Fraser in their starting line-up.
Fraser was one of three Saints changes from the team which drew 1-1 at home to Middlesbrough on Friday, the ex-Blues loanee coming into the team along with centre-half Jan Bednarek and midfielder Joe Aribo. Kyle Walker-Peters, Will Smallbone and Kamaldeen Sulemana dropped out of the XI but were on the bench.
The Blues struck the first shot of the game in the ninth minute but Davis rather scuffed his effort from just outside the area from Massimo Luongo’s cutback. Moments later, the ball was played into Kieffer Moore’s feet in the box but his lay-back to Axel Tuanzebe was intercepted.
Town had had the better of the opening spell, although with Southampton also having periods on the ball but without threatening, while also showing their tendency to give away possession in their own half which led to the Blues’ goal at St Mary’s earlier in the season.
And on 13th minute, the Saints giving the ball away eventually led to Town going in front.
After a Jackson cross from the right had been half-cleared, skipper Sam Morsy clipped a ball to beyond the far post from where Davis unleashed a powerful strike into the top corner of the net at the near post with keeper Gavin Bazunu caught out expecting a cross, although it’s unlikely he’d have stopped it even if he had read it.
But Town’s lead, courtesy of the left-back’s second goal of the season, lasted only a minute.
Adam Armstrong was sent away down the right and his cross found Aribo, who stabbed it through to Che Adams, who beat Vaclav Hladky. Town, and particularly Burgess, complained bitterly that Adams had been offside but to no avail. Replays suggested they had a very strong case.
On 16, Morsy was booked for a foul on Downes not far outside the area, Bree sending the free-kick the wrong side of the post. The Town captain has now been booked 13 times in the Championship with two more leading to a three-match ban.
Having levelled, Southampton were seeing most of the ball and in the 23rd minute, they took the lead.
Stuart Armstrong brought the ball forward on the left and inside before playing a pass towards the right of the box for Adam Armstrong, who reached it and hit it first time across Hladky and into the net, Davis having just failed to take it away from the former Blackburn striker with a sliding challenge. The full-back will feel he should have done better.
Having gone in front, the Saints kept Town penned in their half with their determined pressing, while referee Michael Salisbury’s refereeing decisions continued to antagonise both the Blues’ support and players.
On the half-hour, Davis was sent away in space on the left and played inside to Conor Chaplin on the edge of the box but Town’s 13-goal top scorer scuffed his shot through to Bazunu.
While that move was ongoing, Moore was on the turf having picked up what looked looked like a back problem and the on-loan AFC Bournemouth underwent treatment before returning but while still appearing hampered.
And in the 35th minute, the Wales striker lay down in the Southampton penalty area as Ali Al-Hamadi got himself ready to come on, which the Iraqi international did in the 36th minute as Moore made his way straight to the tunnel.
The stoppages seem to impact the Saints’ momentum and on 38 Town had what looked a decent shout for a penalty.
Al-Hamadi flicked on and Jackson chased into the right of the area and appeared to be tripped by visitors’ skipper Jack Stephens. There might have been a question of whether the offence was in the area but in any case referee Salisbury didn’t see a foul.
However, Southampton quickly got back on top and in the 42nd minute went close to a third goal.
After Town had been forced into losing possession, Downes brought the ball forward and played a pass into Fraser on the left of the box and the Scotland international shot across Hladky but just past his far post.
The Saints continued to control the game as it moved into seven additional minutes with stoppages for soft free-kicks, largely awarded to the visitors, continuing to be frequent.
Adam Armstrong shot over from the right of the box, then a minute before the whistle, Stephens was flagged offside following a corner, leading to widespread sarcastic applause and cheers from the home support in the Sir Bobby Robson Stand and the Cobbold Stand.
At the end of the half there were boos aimed towards the officials with referee Salisbury left in no doubt about how his performance - and that of his assistants - had been judged as he made his way to the tunnel.
Town had started well and scored what had seemed likely to be the game’s vital first goal, Davis hitting an unstoppable strike.
But the Blues immediately allowed the Saints to hit back, Adam Armstrong getting away down the right to create the opportunity which eventually fell to Adams. The assistant on the far side’s vision appeared to be affected by the low sun, which may account for the offside having been missed.
Having got on terms, the Hampshire side had much the better of the rest of the half and Town were fortunate to only go in a goal behind at the break, with Moore’s loss to injury a further blow.
The Blues will be a lot better in the second half if they’re to take anything from the game.
Town: Hladky, Tuanzebe, Woolfenden, Burgess, Davis, Morsy (c), Luongo, Hutchinson, Chaplin, Jackson, Moore (Al-Hamadi 36). Subs: Walton, Edmundson, Clarke, Travis, Taylor, Harness, Sarmiento, Broadhead.
Southampton: Bazunu, Harwood-Bellis, Stephens (c), Bednarek, Bree, Downes, Aribo, S Armstrong, A Armstrong, Adams, Fraser. Subs: Lumley, Walker-Peters, Manning, Smallbone, Rothwell, Brooks, Edozie, Kamaldeen, Mara. Referee: Michael Salisbury (Preston).