Billy Sharp missed a first-half penalty for Saints and they were made to pay a heavy price.
Stephen Dobbie succeeded where Sharp had failed before adding a second on his first appearance at Bloomfield Road since returning to Blackpool on loan from Swansea.
Recalled wing duo Tom Ince and Matt Phillips caused no end of problems for Southampton in an enterprising first-half display and Ian Evatt sealed the points when he was allowed a free header from the latter's corner seven minutes after the interval.
Nigel Adkins' side missed the thrust of injured top scorer Rickie Lambert in attack and Reading's victory over promotion rivals West Ham earlier in the day means their lead at the top has been trimmed to two points.
Blackpool are back in the play-off places on goal difference with six games remaining.
Seasiders boss Ian Holloway made seven changes following last weekend's 3-1 loss at Reading, with Phillips and Ince restored to the starting line-up and Bob Harris handed a first league start for the club at left-back.
Guly Do Prado came into the Southampton attack as Lambert was given time to recover from a slight groin strain picked up in last weekend's win over Doncaster and the Brazilian almost gave the visitors an early lead.
Do Prado outmuscled Evatt to lift a shot over onrushing Seasiders goalkeeper Matt Gilks but saw his effort bounce past the post.
Gilks' opposite number Kelvin Davis then produced a pair of fine saves to thwart Gary Taylor-Fletcher after Phillips and then Ince found joy raiding down the flanks.
Former Liverpool youngster Ince latched on to a raking ball from Taylor-Fletcher to twist Saints full-back Daniel Fox inside out, but Davis was equal to the task when the shot came in at his near post.
Against the run of play Southampton had the chance to go ahead in the 16th minute when the referee's assistant flagged after an untidy challenge from Harris clipped Do Prado's standing leg.
Sharp's spot-kick was well struck but not far enough towards the corner, allowing Gilks to plunge to the right and save comfortably.
Six minutes later, Blackpool had their own opportunity from the spot.
Morgan Schneiderlin was adjudged to have fouled Taylor-Fletcher despite the forward appearing to be off balance when he burst into the box, and Dobbie dispatched the kick with aplomb, beyond Davis' dive into the bottom left corner.
Jos Hooiveld should have brought Southampton level with a close-range header when Richard Chaplow flicked on Fox's corner - a miss that instantly came back to haunt him.
From the resulting goalkick, Taylor-Fletcher won the flick on and Dobbie shrugged Jose Fonte aside before producing another measured finish.
Fonte did just enough to divert Alex Baptiste's header from Ince's 51st minute corner behind, but Evatt immediately cashed in on his centre-back partner's efforts.
Preoccupied with Baptiste's threat, the next corner was arrowed to the back post where Evatt thumped home.
Blackpool briefly threatened to run riot and Dobbie had a shot blocked after Ince and Taylor-Fletcher linked up well.
In the closing stages, Holloway's men saw out the match in relative comfort.
When Southampton did find a way through they were wasteful. Do Prado found space at the back post to tee-up Adam Lallana, but the midfielder uncharacteristically slashed horribly wide.
