The match has prompted the biggest continental exodus in the club's history with 6,700 fans making the 3,000km round trip
Travel chaos is forecast but Southampton fans are unlikely to care as their dream journey from English football's third tier to the Europa League will see them visit Italian giants Inter Milan on Thursday.
The Group K match has prompted the biggest continental exodus in the club's history with 6,700 fans making the 3,000km round trip amid warnings of a threatened national transport strike that is set to disrupt their homeward trek.
Southampton supporters however know there are worse areas than Milan to get stranded, venues like Dagenham, Hartlepool and Walsall come to mind, places they frequented five years ago when their team were in League One.
Now they are not only rubbing shoulders with Europe's finest in Inter, who have 18 Italian top-flight titles and three European Cups to their name, the group leaders also stand an excellent chance of defeating them.
Claude Puel's Southampton have gone seven games unbeaten in all competitions and Sunday's 3-1 win over Burnley in the Premier League saw them concede their first goal in more than 10 hours of football.
Perhaps, most surprisingly, they occupy fourth spot behind Real Madrid, AS Roma and Liverpool in terms of chances created in Europe's big five leagues this season.
Many of those opportunitiesa have fallen to Charlie Austin, a striker on the hottest of streaks with seven goals in his last six games.
Such was his positioning around the Burnley penalty box that he probably should have bagged double his two goals in a performance that drew praise from club great Matthew Le Tissier.
"The mental strength to miss a couple of chances and still want to put yourself in that position is underestimated," said former England international forward Le Tissier.
"Some strikers will miss a couple of easy ones and you won't see them get any more chances because they don't want to put themselves in that position. Charlie is nothing like that."
Southampton face an Inter team who have almost forgotten how to win and are riven by a farcical dispute pitting supporters against striker Mauro Icardi.
Icardi is enduring a nightmare season, with fans cheering when he missed a penalty against Cagliari on Sunday.
They are unhappy with remarks in his recent autobiography about a confrontation with one of the club's 'ultra' leaders in 2015 during which he said the fan ordered a child to hand back the Argentine's shirt after the player had given it to him.
On Tuesday, a group of hardcore supporters issued a statement refuting the suggestion and called on the club to strip Icardi of the captaincy.
During another season, when things may not have been going so badly for Inter, the spat might have been overlooked.
But the club have lost three successive games, are yet to win a point in two matches in the Europa League and have a coach in Frank de Boer whose possession-based style is being questioned.
Inter have looked slow and predictable and are down in 11th place in Serie A.
On the flip side of the coin Southampton, who have never faced an Italian team in a competitive game, will be awash with confidence.
No one will be more excited than left back Sam McQueen who is in line to make his European debut four days after being granted a first Premier League start.
McQueen, a local boy with a Hollywood surname, described Sunday as "a movie-star moment".