While the Saints can move out of the bottom three with a victory, the Bees could climb into the top seven if they claim maximum points on the South Coast.
Match preview
Aside from a disappointing FA Cup exit to fourth-tier side Grimsby Town, Southampton appear to have turned a corner under new boss Ruben Selles, with a slender 1-0 league victory over Leicester City followed by a hard-fought goalless draw against 10-man Manchester United on Sunday.
Despite playing for over an hour with an extra man at Old Trafford, following Casemiro's first-half dismissal for a late tackle on Carlos Alcaraz, the Saints failed to convert any of their 17 shots in an entertaining contest that required both David de Gea and Gavin Bazunu to be on top of their game between the sticks.
Selles expressed his frustrations after coming away with only a point, but Southampton have now kept three clean sheets in their last four top-flight matches and have boosted their hopes of survival by claiming seven points from a possible 12 available - more than twice as many picked up by predecessor Nathan Jones (three) during his dreadful three-month spell in charge.
Despite the draw against Man United, Southampton remain at the foot of the table, but a victory for Selles' revitalised side against Brentford on Wednesday would see them climb out of the bottom three for the first time since November.
With four home games in their next five on the horizon, the Saints will be keen to improve their form at St Mary's having picked up the fewest home points (nine) in the Premier League this season.
Brentford's remarkable 12-game unbeaten league run, dating back to the end of October, was brought to an end by Everton last weekend as they suffered a slender 1-0 defeat at Goodison Park.
Dwight McNeil's strike after just 35 seconds was enough to condemn the Bees to just their fifth league defeat of the season, and Thomas Frank is keen for his side to quickly bounce back from their minor setback as the continue to push for a top-six finish.
Brentford remain ninth in the Premier League table, but a victory on Wednesday could see them climb into the top seven and move to within one point of sixth-placed Liverpool, who the Bees will face on the final day of the campaign.
While Brentford have excelled in front of their own fans this season, losing only one of their 13 Premier League home games, they have struggled to come out on top on the road as they have won just two of their 12 away matches. The Bees also suffered a 4-1 defeat to Southampton in their last visit to St Mary's in January 2022.
However, Frank and co breezed past the Saints in their most recent meeting last month, securing a 3-0 victory on home soil, and another win on Wednesday will see them record back-to-back league wins against their South Coast counterparts for the first time since March 1959.
Southampton Premier League form:
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Southampton form (all competitions):
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Brentford Premier League form:
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Team News
Southampton will still be without Valentino Livramento (ACL) and Juan Larios (muscle) as they continue to recover from long-term injuries, while Selles is hopeful that Ainsley Maitland-Niles will recover from a minor "issue" that kept him out of the draw at Man United.
James Bree, Lyanco and Mislav Orsic all played for the B Team last weekend and will be hoping to return to the senior matchday squad on Wednesday.
Selles is unlikely to make too many changes, if any, to his starting lineup, with Theo Walcott, Kamaldeen Sulemana and Che Adams all set to continue in attack, although the likes of Paul Onuachu, Adam Armstrong and Sekou Mara will all be pushing to start.
As for Brentford, their only injury concerns are with Thomas Strakosha (ankle) and Keane Lewis-Potter (knee), the latter of whom recently underwent surgery.
Frank could stick with the same back four of Aaron Hickey, Ethan Pinnock, Ben Mee and Rico Henry that started against Everton, although one of Pontus Jansson or Kristoffer Ajer could return to the first XI should the Bees boss decide to switch to a back three.
Yoane Wissa and Kevin Schade will be pushing to start in attack ahead of Mikkel Damsgaard, while Bryan Mbuemo - who scored against Southampton last month - is expected to continue alongside top scorer Ivan Toney.
Southampton possible starting lineup:
Bazunu; Walker-Peters, Bella-Kotchap, Bednarek, Perraud; Lavia, Ward-Prowse, Alcaraz; Walcott, Adams, Sulemana
Brentford possible starting lineup:
Raya; Hickey, Pinnock, Mee, Henry; Jensen, Norgaard, Janelt; Mbeumo, Toney, Wissa
We say: Southampton 1-2 Brentford
Southampton's resilience at the back has been a major factor behind their recent upturn in form under Selles, but adding goals to their game is required if they wish to climb out the drop zone, having scored only three times in their last seven league matches.