Just three days after ending Arsenal's FA Cup defence in the fourth round, Southampton welcome the Gunners to the South Coast once again in the Premier League on Tuesday evening.
An own goal from Arsenal defender Gabriel Magalhaes was all that separated the two sides at St Mary's on Saturday, as the Saints claimed a deserved 1-0 win over the FA Cup holders.
Mikel Arteta masterminded Arsenal's record-breaking 14th FA Cup triumph less than seven months into his Emirates tenure, but the Spaniard was forced to witness his below-par team relinquish their crown in the fourth round at St Mary's.
There was certainly an element of fortune about Southampton's winner as Kyle Walker-Peters's cross deflected off Gabriel into the Arsenal net, but Ralph Hasenhuttl's compact and well-oiled machine deserved no less than a win on Saturday, and Saints fans will now be licking their lips at the prospect of a memorable cup run.
A morale-boosting win was just what the doctor ordered for a Southampton side who have started to falter in the league, as they can only boast one victory from their last six in the top flight, although that was their historic triumph over Liverpool earlier this month.
Leicester City stamped their authority on Hasenhuttl's side last weekend to leave them 10th in the table - level on points with Chelsea, who have played a game more - but the Saints remain just three points adrift of the top six as the battle for a European berth hots up.
Despite the recent loss of Jannik Vestergaard, Southampton's resolute defence recorded a fourth consecutive home clean sheet in all competitions with Saturday's 1-0 win, and only Manchester City, Liverpool and West Ham United have collected more points on their own patch this season.
Arsenal boss Arteta handed opportunities to several fringe players at St Mary's, but the Gunners were second best throughout much of the tie as their love affair with the FA Cup ended at the second hurdle - for this season at least.
The defeat comes as a devastating blow to an Arsenal team who have certainly upped their game in recent weeks, but with Arteta set to recall some of his big-hitters to the lineup on Tuesday, Gooners should be able to enjoy a more assured performance from their side in midweek.
As one of only five teams in the top flight not to have lost any of their last five matches, the Gunners have quashed any faint whispers of relegation and are firmly in the mix for a Europa League spot alongside Southampton - with two points separating the clubs ahead of Tuesday's game.
Arteta has witnessed his crop march to victory in four of their last five Premier League matches - conceding only once in that time - and their tally of 19 league goals shipped is the fourth-lowest in the division.
Victory for Arsenal here would see them temporarily rise above Southampton, Aston Villa and Chelsea into eighth before the latter two teams play on Wednesday, but having already suffered one defeat on the South Coast this season, a rejigged Gunners side must have their wits about them if they are to get their instant revenge.
Southampton Premier League form: DLDDWL
Southampton form (all competitions): DDWLWW
Arsenal Premier League form: LWWWDW
Arsenal form (all competitions): WWWDWL
Hasenhuttl's strong lineup on Saturday was certainly a statement of intent from the Saints manager, and it would be a surprise to see many changes from the XI that put in a solid display against the Gunners.
The St Mary's infirmary is well-occupied at the moment as Vestergaard, Moussa Djenepo, Mohammed Salisu and Oriol Romeu continue to nurse various injuries.
Hasenhuttl conceded that none of the Saints' injured players is likely to return in time for this one barring Nathan Redmond, and he will also be without first-choice full-backs Ryan Bertrand and Kyle Walker-Peters through suspension and injury respectively.
Arsenal skipper Pierre-Emerick Aubameyang had to attend to a personal matter over the weekend, and the striker will not line up on Tuesday either.
Dani Ceballos and Pablo Mari have both been ruled out with calf problems, but Arteta will no doubt revert to his strongest XI in the hope that lightning does not strike twice at St Mary's.
Thomas Partey, Kieran Tierney, Emile Smith Rowe, Bukayo Saka and Alexandre Lacazette should all return to the fold, while Gabriel Martinelli could be handed another start on the left with Aubameyang out.
However, Tierney is a fresh doubt for this game after suffering from discomfort in his right calf, but Arteta will hope to have him available.
Southampton possible starting lineup:
McCarthy; Valery, Bednarek, Stephens, Vokins; Walcott, Diallo, Ward-Prowse, Armstrong; Ings, Adams
Arsenal possible starting lineup:
Leno; Bellerin, Holding, Gabriel, Tierney; Xhaka, Partey; Saka, Smith Rowe, Martinelli; Lacazette
Source: Sports Mole / Ben Knapton