The South Coast club struggled to create any meaningful chances in the encounter, and the Bees defended resolutely in the second period before doubling their advantage late on.
Ivan Toney opened the scoring in the first half for Thomas Frank's side, and then the striker turned provider for substitute Yoane Wissa, who put the result beyond doubt in added time.
It was a scrappy start to proceedings at St Mary's, with neither team having a sustained period of possession on a slippery playing surface, despite the right endeavour from both sides.
Kevin Schade - making his first Premier League start for the Bees - had the first notable chance of the contest, with his looping header set up by Mathias Jensen unable to test Gavin Bazunu in the Saints net.
Jensen provided another tempting cross not long after, and this time it was marksmen Toney who scuffed his strike - although the linesman had raised his flag on the England striker.
The visitors continued to push their relegation-threatened hosts, with Bazunu denying Bryan Mbeumo from close range, although the Saints' resistance could only go on for much longer.
Cameroon international Mbeumo sent in a scrumptious corner-kick delivery which was flicked on by Christian Norgaard, and it was Toney who was arriving at the back post to score his 16th goal in the Premier League this season.
Having failed to muster a shot on target during a disappointing first-half showing, Southampton were denied an equaliser early in the second period by some last-ditch defending from Ben Mee and David Raya, with the Brentford duo managing to clear Che Adams's effort off the line.
A triple substitution soon followed for the struggling Saints as the hour mark approached, with Theo Walcott, James Bree and Romeo Lavia all entering play as Ruben Selles looked to change his team's fortunes.
The hosts quickly reverted to a more direct approach of attack as time ran out to find a leveller, with Nigerian forward Paul Onuachu being the main target for Southampton's wide players.
Selles's men gained further territory in the closing stages of the contest but were ultimately unable to breach Raya's net, and in truth, the hosts will be disappointed with their attacking play overall.
The Bees then doubled their lead to send the away end into hysterics, with a clever Toney flick setting substitute Wissa through on goal, and the 26-year-old sent his strike past the unprotected Bazunu.
Southampton welcome Tottenham Hotspur to St Mary's in their final match before the first international break of the calendar year, whereas Brentford host Leicester City as they continue to hunt down those coveted European places.