Arsenal secured a vital victory over Manchester United on Sunday to keep their Champions League hopes alive and it's imperative that they win their final four league games if they want to secure a top four spot.
Ozil: My future? Top four is all that matters
Wenger finally ending his curse against Jose Mourinho with a comprehensive 2-0 win at Emirates Stadium where goals from Granit Xhaka and Danny Welbeck sent Arsenal on their way to pick up three points.
The game against Southampton represents a different type of task as Claude Puel's side technically do not have a Europa League place to play for which means rotation in the Frenchman's side is likely after Sunday's stalemate with Liverpool at Anfield.
However, Wenger's side have lost five of their last six away Premier League games – the same number they’d lost in their previous 27 on the road in the competition - and need that disappointing record to change if they want to win on Wednesday.
Granit Xhaka is a fitness doubt ahead of Wednesday's game but Shkodran Mustafi could return to the team after recovering from injury.
Szczesny should be Arsenal's No.1
Wantaway forward Lucas Perez is another player back in contention although it's unknown whether he'll feature again this season.
French youngster Jeff Reine-Adelaide is ruled out until the end of the season with an ankle injury, with Santi Cazorla another long-term absentee.
ARSENAL POTENTIAL STARTING LINE-UP
Danny Welbeck looks set to continue up front after his goalscoring performance against Manchester United on Sunday.
Wenger questions Chelsea style
The England forward produced a confident display in the match versus his former club and he will be hopeful of starting every game until the end of the season now.
Meanwhile, it's likely that Wenger will stick with the core of the team which beat United while sticking with three at the back.
Southampton are in the secure position of knowing that they have secured a mid-table spot in the Premier League table with just four matches of the season remaining.
Ozil makes child's dream come true
Claude Puel's side put in an impressive defensive shift against Liverpool at Anfield on Sunday and will look to draw inspiration from that game when they come up against an improved Gunners side.
Puel has no new injury concerns ahead of Wednesday's match, although admits there is a 'little tiredness' in the camp and could be forced to rotate players to freshen things up.
Virgil van Dijk (foot) and back-up goalkeeper Alex McCarthy (hamstring) are still out through injury.
Charlie Austin is their top scorer with 9 goals this season.
BEST OPTA MATCH FACTS
Southampton are looking to win three consecutive home league matches against Arsenal for the first time since 1985.
Arsenal are winless in their five previous away visits to St Mary’s in the Premier League, last winning there in December 2003 (D3 L2).
Arsene Wenger has won only 25% of his Premier League games at St. Mary’s (two of eight) as opposed to 60% at the Dell (three of five).
However, the Gunners did beat Southampton 5-0 away in the fourth round of the FA Cup this season. Theo Walcott scored a hat-trick in that match, while Danny Welbeck got the other two.
Southampton have managed just 10 shots on target across their last five Premier League games and recorded none against Liverpool in the 0-0 draw on Sunday.
Alex Oxlade-Chamberlain has provided seven assists for Arsenal in the Premier League, including two in his last match against Manchester United. This is the same total as his previous five seasons combined with Arsenal.
TV COVERAGE & KICK-OFF TIME
Kick-off is at 19:45 BST on Wedneday, 10 May and the match is not being broadcast live on TV in the UK.