The Saints have struggled against the big teams this season and are yet to pick up three points against one of them but, considering their good record at home to Arsene Wenger's side, will be hopeful of causing an upset.
With just a couple of weeks left in the Premier League season, it is crunch time for multiple teams, as they desperately attempt to make the season a successful one.
For Southampton, it has not been a campaign to write home about. A run to the EFL Cup final aside, manager Claude Puel's inaugural season in English football has been mediocre at best.
At a glance, one would be forgiven for believing Southampton had had a decent season. The South Coast outfit currently sit in tenth place, and could very feasibly finish as high as eighth. However, the quality and style of football under Puel has been less than impressive, with the Saints struggling to score enough goals and regularly refusing to take the game to their opponents. Moreover, the Frenchman has come under intense criticism for his constant rotation of his squad. This means that, after finishing in sixth a year ago, Southampton's campaign this time around feels like a step back.
While Southampton have little to play for going into the final stretch, their opponents tonight are enduring a bloody battle for Champions League football next season. Arsenal could close the gap between themselves and fourth place to just three points with a win at St Mary's, but a loss would all but end their hopes of playing in Europe's elite competition come the Autumn.
After another season of under-achievement, sneaking into the top four, combined with an FA Cup final victory over Chelsea in three week's time, would just about make it an acceptable season for Wenger and the Gunners. Consequently, a victory tonight is a necessity.
Looking to spring a surprise
While far from the main failure for Puel and his team this season, the Southampton faithful will be unhappy with the fact that they have been unable to beat a top six side in the league.
Aside from Leicester, the Saints beat every team that finished above them last time around, as well as victories over Chelsea and Liverpool, and so the absence of a memorable upset this campaign has been somewhat disappointing.
However, if Southampton are to pull out an unlikely win, it would surely begin against Arsenal. The Gunners have lost on their last two trips to St Mary's in the league, most notably getting hammered 4-0 last season.
Tonight's hosts' strong record against their visitors may give them the psychological edge required to beat one of the big boys at last.
Aside from the on-going issues for Virgil Van Dijk, Charlie Austin, Matt Targett and Alex McCarthy, Claude Puel has no injury concerns.
Midfielder Granit Xhaka should be fit for the Gunners after picking up a calf problem against Manchester United on Sunday, but centre-back Laurent Koscielny could miss out with a similar knock.
There's history between them
Claude Puel's mentor in management was none other than Arsene Wenger.
Both Theo Walcott and Alex-Oxlade Chamberlain are products of the Southampton academy, and were subsequently sold on to Arsenal.
Despite their recent struggles at St Mary's, Arsenal were 5-0 victors the last time the two teams met, as they outplayed a very under-strength Southampton side in the FA cup in February.