The Shrimpers went down to 10 men after left-back Ben Coker was dismissed in the 67th minute of the match for a foul on Hatters substitute Shaun Whalley.
But they dug deep and secured all three points with Michael Timlin bagging a bizarre winner nine minutes from time.
Timlin’s 25-yard shot was fired straight at Elliot Justham, but the Hatters goalkeeper somehow let the effort trickle into the back of the net to secure Southend a seventh successive win.
The loss means Luton’s play-off hopes are now all but over barring a huge swing on goal difference on the final day of the season.
However Phil Brown’s side are now two points clear of Bury in fourth place after a run of eight clean sheets in a row, and can secure automatic promotion with a win at Morecambe next week.