Two goals from Brazilian Guly do Prado at St Mary's ensured that Southampton remain top of the Championship.
Saints dominated the first half, only a fine save from Julian Speroni preventing Rickie Lambert from breaking the deadlock with a stooping header.
However, do Prado put them in front by heading in Steve de Ridder's cross.
Shortly after the break do Prado was denied by a last-gasp Patrick McCarthy block, but the playmaker soon headed in again from a Frazer Richardson cross.
Victory extended Southampton's unbeaten home run to 24 matches - and they never looked in danger of defeat against a Palace side who .
Saints made one change to the side held to a on 18 December, De Ridder coming in for captain Dean Hammond.
Jose Fonte was named skipper against former club Palace, who made several changes, including the recall of highly-rated Wilfried Zaha after suspension.
Lambert might have scored inside nine minutes with a powerful header from Morgan Schneiderlin's superb right-footed cross to the far post, but Speroni reacted well with a point-blank save.
However, De Ridder surged down the right flank, turned Peter Ramage inside out and drove in a cross for do Prado to grab the opening goal.
After do Prado was denied by McCarthy's block, Adam Lallana shot narrowly wide, while at the other end referee Graham Salisbury rejected an appeal for handball against Richardson and Glenn Murray forced Kelvin Davis into a save.
However, do Prado made sure with 13 minutes remaining, nodding in from Richardson's right-wing cross.
Southampton manager Nigel Adkins:
"There were two good goals. I think we dominated the first half and, in the second, we started brightly again before it got a little bit scrappy.
"But a good second goal from do Prado and we saw the game out quite comfortably. I am pleased we kept a clean sheet.
"Our endeavour will be to enhance the squad we have got [in January] but we have an exceptionally good team spirit, which has been demonstrated again today. We have a close-knit group that all want to be successful together."