Billy Sharp scored twice as Southampton took another step towards automatic promotion to the Premier League.
Jos Hooiveld opened the scoring with a header from a corner before Sharp rifled into the roof of the net.
Sharp then added his second from close range after Adam Lallana picked him out at the back post with a superb pass.
Tommy Rowe hit a late consolation for the hosts but the win leaves the Saints five points clear of third-placed West Ham with two games remaining.
Nigel Adkins' side, who host struggling Coventry on the final day, know they can secure automatic promotion as soon as Saturday when they head to Middlesbrough.
They took control from the start, with Hooiveld beating Paul Jones from Dan Fox's corner for his seventh of the season.
Five minutes later they were two ahead when Lallana managed to stay on his feet and cross for Richard Chaplow, who teed up Sharp to thump in.
After standing firm against Peterborough's attempts to respond, the Saints made it three just before the hour.
Rickie Lambert's cross-shot fell for Sharp, who guided in for his 17th of the season and his sixth in six games.
Rowe did manage to pull one back when he converted from six yards from a Tyrone Barnett cross.
It was a third straight defeat for Posh, but results elsewhere meant they are guaranteed to be playing second-tier football next season.
Southampton boss Nigel Adkins: "It was a good victory away from home and the players deserve great credit for that.
"It was a thoroughly professional display and an excellent response to the defeat against Reading on Friday.
"We are not concerning ourselves with results elsewhere or the amount of points we may need to secure promotion.
"We have two matches left and we want to put six more points on the board. Our aim has always been to be champions and that hasn't changed."
Peterborough boss Darren Ferguson on securing Championship safety: "It is our biggest achievement as a club by miles.
"But it is a very different feeling to winning promotion. This is more about relief than joy.
"We have stayed up because we were outstanding in the first half of the season.
"We haven't been great lately but always knew the effects of having such a short break after winning the League One play-offs last summer would catch up with us."