Thomas Frank’s side, usually a match for any opposition, fell to a concerning defeat in relatively meek fashion despite leveling the score after initially falling behind.
Goals from Jan Bednarek, Armando Broja and Che Adams, plus an own-goal from Bees goalkeeper Alvaro Fernandez, secured a resounding victory in Saints’ first top-flight outing since last week’s takeover.
Brentford midfielder Vitaly Janelt briefly levelled proceedings with a fine first-half volley but the evening belonged to Ralph Hasenhuttl’s rampant hosts.
Victory for Southampton – secured in front of lead investor Dragan Solak – moved them to 11th in the table, a point and two places above their opponents.
The emphatic result was the first time Saints had managed more than three league goals in a game under Hasenhuttl.
A new era for the south-coast club started in rather subdued fashion with Saturday’s gruelling extra-time FA Cup win at Swansea, which was played behind closed doors due to coronavirus restrictions in Wales.
This was their first outing on home soil since investment firm Sport Republic acquired an 80 per cent stake and proved to be a far more fitting occasion.
Southampton, who opted for an unfamiliar 3-5-2 wing-back system in the absence of a recognised right-back, made a perfect start inside five minutes.
Captain James Ward-Prowse delivered an inviting, inswinging corner from the left and in-form defender Bednarek found space to glance home his third goal in five Premier League games.
Brentford have struggled for results on the road in recent months and arrived in Hampshire with just two points from the last 15 available away from home.
Thomas Frank’s men looked set for a difficult evening following their slow start but needed just 18 minutes to restore parity as Bryan Mbeumo and Janelt – two of four players recalled following the 2-1 win over Aston Villa on January 2 – combined to devastating effect.
Buoyed by his hat-trick in Saturday’s 4-1 FA Cup win at League Two Port Vale, Mbeumo crossed from the right, allowing unmarked German Janelt to stylishly volley into the bottom left corner from 10 yards.
That was to be the high point for the west London club and they fell behind for a second time in the 37th minute, this time in slightly unfortunate fashion.
After a Ward-Prowse corner was only partially cleared, midfielder Ibrahima Diallo hit a fizzing shot from the edge of the box which struck the left post before rebounding into the net off the diving Fernandez.
Spaniard Fernandez then partially redeemed himself by clawing out Broja’s goal-bound header but was unable to deny the same player just four minutes after the restart as Saints broke away to stretch their advantage.
After Brentford carelessly conceded possession deep in Saints territory, Chelsea loanee Broja raced clear from halfway following Oriol Romeu’s through-ball before calmly slotting into the bottom right corner.
Substitute Adams – back in action following coronavirus – added further gloss to the scoreline by lifting the ball beyond Fernandez 20 minutes from time following Diallo’s hopeful punt forward.
Brentford pushed hard to make the scoreline more respectable but they were kept out by some dogged defending as Saints’ jubilant supporters celebrated a memorable evening by lighting up the stadium with their phones
Additional reporting from PA