The Hatters had already gone down to League One before the match, but the win gave Kevin Blackwell his first win in six games since replacing Mike Newell at Kenilworth Road.
An even opening spell ended with the visitors from Bedfordshire taking the lead on 20 minutes.
Lively left winger David Bell avoided Kevin Maher's challenge and broke down the flank, before a pin point cross picked out striker Calvin Andrew, who shot home into the bottom left-hand corner of the goal.
Bell was the architect of The Hatters second on 39 minutes when his dangerous cross from the left was cleared by defender Adam Barrett only as far as Matthew Spring, who chested the ball down before curling it to the top right hand corner of Darryl Flahavan's goal.
Southend went into the match without the influential Freddy Eastwood and Mark Gower, who were both injured, and their problems were compounded when skipper Maher also went off with an injury.
But the Shrimpers fought back after the break and created some good chances before striker Lee Bradbury handed them a lifeline.
A Steve Hammell shot was cleared off the Luton goalline and fell to Bradbury, who struck home with a left-foot half-volley.
However, any hopes Southend had of finding a route back into the game were ended on 87 minutes when Spring's upfield ball allowed striker Besian Idrizaj to beat the offside trap and calmly slot past Flahavan in a one-on-one situation.