Ben Mee and Bryan Mbeumo scored late in the first half to set Brentford up for a third-straight home Premier League victory.
After being frustrated for much of the opening period, Mee headed home an Mbeumo cross to open the scoring shortly before the break.
The provider then turned scorer three minutes later, converting Yoane Wissa’s low cross.
Southampton rallied after the break without ever truly threatening a comeback.
It was then left to Mathias Jensen to wrap up the game with 10 minutes to play with a deft header.
The result, which extended Brentford’s unbeaten league run to nine matches, lifted Thomas Frank’s side above Fulham and up to seventh in the top flight.
Hickey and Wissa in for Ajer and Roerslev as Frank opts for 4-3-3
Brentford were able to name Aaron Hickey in a starting line-up for the first time since October.
He replaced Kristoffer Ajer as Frank reverted to a back four. The other change saw Wissa come in for Mads Roerslev.
Southampton made four changes from their Carabao Cup semi-final defeat to Newcastle United.
Kyle Walker-Peters missed out through injury; his place going to Romain Perraud.
Elsewhere, Samuel Edozie, Mohamed Elyounoussi and Romeo Lavia were also restored to the Saints line-up as Nathan Jones also set his side up with four in defence.
Brentford: Raya; Hickey (Roerslev 61), Pinnock, Mee, Henry; Norgaard, Jensen (Damsgaard 82), Dasilva (Janelt 61); Mbeumo (Zanka 82), Wissa (Schade 74), Toney
Subs not used: Cox, Ghoddos, Ajer, Lewis-Potter
Southampton: Bazunu; Bree, Bednarek, Salisu, Perraud; Lavia (Alcaraz 65), Diallo (Kamaldeen 46), Ward-Prowse; Edozie (Walcott 65), Elyounoussi (Onuachu 46), Adams (Armstrong 81)
Subs not used: Caballero, Maitland-Niles, Lyanco, Aribo
Attendance: 17,051
Brentford end first half with a flourish
Given the respective form of the two sides, it was no surprise that Brentford started on the front foot.
The Bees forced a succession of early corners as Southampton struggled to contain the movement in midfield of Josh Dasilva and Jensen.
The returning Hickey had the first effort of the afternoon from Dasilva’s deep cross - a Southampton defender quickly out to make the block.
Brentford’s next attack saw them the width of the crossbar away from an opener – Ivan Toney’s dinked through ball was collected by Wissa but, having rounded Bazunu, he could only lift his effort onto the face of the bar from eight yards.
To counter the Bees’ threat, James Ward-Prowse was playing in a more advanced role, trying to join Che Adams in the Saints’ press. However, that meant that Lavia and Ibrahima Diallo were often two against three in the middle and Brentford took advantage.
Dasilva in particular was enjoying the space afforded to him and he was a key part of a flowing Brentford move which almost brought the opener. Receiving Jensen’s pass, he drove forward and found Wissa. The winger’s cross was met by Toney who, not for the last time on the afternoon, saw his goal-bound effort blocked by Mohammed Salisu.
For their lack of threat in the opening 15 minutes, Southampton carved out a huge opening the first time they really ventured into Bees territory. Ward-Prowse collected a lofted pass in behind but chose to square rather than shoot from the angle on the left. Adams was all alone for the tap-in at the back post, but the ball was slightly behind the striker and ran away to safety.
After Brentford’s fast start, Southampton steadied themselves, keeping the Bees at arm’s length.
Aside from Mbeumo’s scuffed shot across goal and a Samuel Edozie shot, blocked by Christian Norgaard, neither goal came under real threat during the middle portion of the half.
Brentford were without doubt the side looking more dangerous and they cranked up the pressure once again as half-time approached.
Dasilva’s driving runs continued to be Southampton’s undoing, those in blue unable to keep pace with the Bees’ no.10 once he had got away from them on the half-turn.
Dasilva was crowded out as he went to shoot from a Mbeumo lay-off before turning provider for Toney, Salisu again with a last-ditch intervention to divert the ball away from goal.
However, there was nothing Salisu, or any other Southampton defender could do four minutes before the interval. Mbeumo teased in an away-swinging cross from the left which begged to be attacked, and Mee did just that. The defender got up above Salisu and Mohamed Elyounossi to power home his third of the season.
The goalscorer, alongside both Saints defenders, were injured in the fully committed challenge, leading to a three-minute stoppage. When play resumed, Brentford needed just 23 seconds to score again.
Hickey’s battling on the touchline saw the ball run loose to Dasilva. He drove over the half-way line before switching it straight onto the toe of Wissa on the left-edge of the box. The DR Congo winger shifted the ball onto his right and rolled it into the path of Mbeumo to sweep home.
Jensen header puts Bees out of sight
The advantage was no less than Brentford deserved and forced Southampton into changes at half-time.
New signings Kamaldeen Suleman and Paul Onuachu were introduced by Jones with immediate impact.
While he was well marshalled by Ethan Pinnock and Mee, Onuachu’s physical presence gave Southampton a focal point alongside Adams, while Kamaldeen looked to add threat from wide.
It was the latter who had Southampton’s first effort on target, a low strike from 25 yards which Raya collected.
Shortly after Raya was in action again, beating away Romain Perraud’s cross-shot into the path of Ward-Prowse who whipped over from 30 yards.
With Southampton pushing on, Brentford were happy to look for opportunities on the counter attack.
Rico Henry had a right-footed shot blocked while, at the other end, Mee got in the way of Carlos Alcaraz’s firm drive.
Frank’s side would have put the game to bed with 20 minutes to play were it not for Salisu’s third goal-denying intervention of the afternoon on Toney; the defender retreating to clear after Toney had collected Mbeumo’s quick free-kick.
Having almost been completely out it, Southampton then had two golden chances to very much get back into the game.
A combination of Mads Roerslev and Pinnock kept Walcott’s close-range effort out following Raya’s half-clearance of a Ward-Prowse free-kick.
The Bees stopper was much more decisive in his next action, racing out of his box to block another Walcott effort, with the loose ball eventually headed wide by Adams.
Any nerves around the Gtech were put to bed 10 minutes from time. The goal was brilliant in its simplicity; Henry’s floated centre met by a perfectly timed Jensen run and a deft header that kissed the inside of the post on its way in.
A third straight home Premier League win was in the bag and both sides knew it.
As the game approached stoppage-time, Onuachu got the better of Pinnock for the first time in the half but floated his header into Raya’s gloves.
Roerslev could have added a fourth on the break, but he drilled his shot over the bar from the right-hand angle of the box with men waiting in the middle.
There was still time for one more regulation Raya save to deny Armstrong, a significant action as it confirmed the Spaniard’s 50th clean sheet for Brentford which, alongside the three goals and three points, made it another excellent day for Frank’s side.
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