New boy Pablo Daniel Osvaldo netted his first goal for the club to give the hosts the lead just two minutes after the interval after an even first half.
And when Rickie Lambert curled in a sensational free-kick just two minutes later, they were on course for victory in front of a 30,699-strong crowd.
Southampton manager Mauricio Pochettino made just one change from the side that sealed a shock 1-0 win over Liverpool last weekend with Steven Davis taking the place of the more attacking Jay Rodriguez.
Palace boss Ian Holloway, meanwhile, made four changes with Damien Delaney injured and Adlene Guedioura also not included, while the conditions of Jason Puncheon's loan deal meant that he missed out against his parent club.
Jimmy Kebe was handed his first start since joining from Reading.
The home side were the first to threaten, with Morgan Schneiderlin seeing a fine effort headed off the line by former Portsmouth player Joel Ward with just five minutes gone.
The south-coast side continued to press, though, and they began to dominate the possession before threatening again shortly afterwards through Lambert.
The England international came into the game with just one league goal so far this season, but he missed a chance to add another in the 23rd minute as he fired just over the crossbar from the edge of the box.
The visitors became increasingly frustrated as the half wore on, typified by a booking for Marouane Chamakh in the 29th minute as he was penalised for simulation when he went down in the area claiming a penalty.
Things looked set to get worse for Palace when Victor Wanyama teed up an effort a few seconds before half-time, only to fire way wide.
Whatever was said in the dressing room clearly served to reinvigorate the hosts, as just two minutes after the restart they went ahead through Osvaldo.
The Italy international did not hesitate after being played in by Adam Lallana, firing home from the edge of the box.
And things got even better for Pochettino's side, two minutes later when Lambert smashed home a sensational free-kick, leaving goalkeeper Julian Speroni with no chance.
Palace manager Holloway made two substitutions in an attempt to gain a foothold back in the game, with Cameron Jerome and Jerome Thomas replacing Barry Bannan and Dwight Gayle.
The switch-up did have an effect, but they could not get past a determined Southampton defence.
Their best chance went begging when Chamakh failed to connect with a cross from Thomas in the 63rd minute.
Southampton looked to have added a third when Rodriguez tapped over the line in the 85th minute, only for the effort to be ruled out for offside.
