Billy Sharp made it 17 goals for the season with a brace at London Road.
Early goals from defender Jos Hooiveld - his seventh of the season - and Sharp set the visitors on their way.
Sharp's second all but sealed the points, with a late strike from Tommy Rowe little more than consolation for the home side.
Peterborough named Gaby Zakuani in their starting line-up despite manager Darren Ferguson suggesting the defender's season was over after he dislocated a shoulder against Leeds at the weekend. Lee Tomlin also started, while Saints named an unchanged line-up.
Southampton took the lead from the first chance of the night. An inswinging corner from Dan Fox found Hooiveld and his downward header beat Paul Jones.
Nigel Adkins' side doubled their lead five minutes later when Adam Lallana burst into the area and could have gone down under challenge. He stayed on his feet and managed to dig out a cross to Richard Chaplow who nudged the ball to Sharp and he slammed home.
Lallana saw a 25-yard drive tipped over by Jones moments later, before Peterborough finally responded.
Tyrone Barnett sent a header straight at Kelvin Davis in the Saints goal and Zakuani forced the keeper into a decent stop with another headed effort shortly afterwards.
First half chances dried up after that, with George Boyd's blocked shot the closest either side came.
Posh started the second half on top, with Shaun Brisley heading into the arms of Davis and Barnett nodding past the left hand post from Boyd's centre.
But Southampton stepped it up and added a simple third in the 57th minute when Rickie Lambert's cross-shot found its way to Sharp and he slid in his second of the night and sixth goal in as many games.
Hooiveld was forced off through injury after 63 minutes but it did not seem to affect the visitors as Chaplow almost added a fourth with a fierce right foot shot which Jones palmed away.
Paul Taylor, who had looked the player most likely to breach the Saints defence, forced a decent save from Davis when he fizzed in a 25-yard shot as time ticked on.
Rowe should have done better with a shot from inside the area in the 85th minute, and after Taylor had stung the palms of Davis again, Rowe did manage to pull a goal back.
A low cross from Barnett was coolly converted by Rowe from six yards.