Freddy Eastwood's 11th goal of the season and a first strike for on-loan Alan McCormack gave the Shrimpers their first win since the 3-1 triumph over Sunderland in August.
Grzegorz Rasiak's 14th strike of the campaign proved only a consolation as Southampton lost to the Blues for the first time in 49 years.
In the early stages Eastwood's 18-yard shot flew just over the bar, but the high-flying Saints then grabbed the match by the scruff of the neck.
The Shrimpers hardly got a look in as striker Bradley Wright-Phillips had three chances but found Darryl Flahavan in the home goal up to the task.
But the Blues weathered the early pressure before getting a grip on proceedings.
Eastwood and Lee Bradbury both went close before Mark Gower passed to Eastwood and he unleashed a 25-yard right foot shot that Saints keeper Kelvin Davies got a hand to but could not keep out.
The Shrimpers should have increased their lead after the break, but McCormack's goal-bound drive was inadvertently blocked by Efe Sodje and Bradbury blazed over when a pass to a well-placed Eastwood would have been the better choice.
George Burley brought on Kenwyne Jones and Inigo Idiakez to up the pressure and it worked as Southend were forced to defend in numbers.
The visitors should have levelled after 64 minutes but Flahavan produced a point-blank parry to deny Rasiak and Sodje blocked Chris Baird's follow-up.
A minute later Saints were 2-0 down as Eastwood teed up McCormack to unleash a curling 25-yard effort that beat Davis' dive.
Saints maintained their pressure, playing four up front, and Rudi Skacel had the ball in the Blues' net on 67 minutes but the assistant referee ruled it out for handball.
Southend were satisfied to exploit the spaces on the break and went close through Bradbury and Eastwood, who were denied by fine Davis saves, while at the other end Wright-Phillips hit the left post.
Top scorer Rasiak finally breached the hosts' defences after 87 minutes when he latched onto Gareth Bale's throw and scored from close range.