At a time when the Saints sit in fourth place in the standings, Stoke are down in 17th spot and needing one win to secure their second-tier status for another 12 months.
Match preview
While edging ahead of two of the top three was always going to prove difficult, Russell Martin will be concerned with the drop off in form of his Southampton players.
Letting slip a one-goal lead to lose at Cardiff City was followed by a 5-0 hammering at the hands of promotion rivals Leicester City on Tuesday night.
As a result, the Saints are effectively consigned to a playoff spot - fourth position to be exact - with West Bromwich Albion, Norwich City or Hull City likely to be their opponents in the semi-finals.
For now, Martin will not be looking that far ahead. This is a team that has lost six of their last 13 matches in the Championship, the majority coming away from St Mary's.
On a positive note, Southampton have won 15 of their 22 league fixtures at their South-coast home, including four of their last five.
Meanwhile, opponents Stoke have been able to move themselves to the brink of avoiding relegation to League One having lost just one of their most recent six fixtures.
Although that included a four-game streak without success, posting three draws kept things ticking over ahead of a potentially-pivotal game with Plymouth Argyle last weekend.
Steven Schumacher was able to get one over his former club as the Potters recorded a 3-0 victory at the bet365 Stadium, establishing a four-point gap with two matches remaining.
Should Birmingham City fail to defeat Huddersfield Town, a draw will be enough for Stoke, but Schumacher will want his Stoke players to build on the seven-point haul that has come from their last four away encounters.
Southampton Championship form:
D
W
W
W
L
L
Stoke City Championship form:
W
D
D
L
D
W
Team News
Joe Rothwell has joined Southampton midfielder Stuart Armstrong on the sidelines ahead of this contest.
Will Smallbone should return in one of several changes made by Martin, with Samuel Edozie and Ryan Fraser also pushing for opportunities.
Ryan Manning could feature at left-back, resulting in Kyle Walker-Peters moving to the right and James Bree dropping to the substitutes' bench.
With Stoke having impressed in seeing off Plymouth, Schumacher could plausibly select an unchanged starting lineup.
Wouter Berger and Mehdi Leris are each in contention for recalls having contributed a goal or assist as substitutes in that game.
The trio of Lynden Gooch, Ben Pearson and Ryan Mmaee will all remain sidelined through injury.
Southampton possible starting lineup:
McCarthy; Walker-Peters, Harwood-Bellis, Bednarek, Manning; Smallbone, Charles, Aribo; Edozie, Armstrong, Fraser
Stoke City possible starting lineup:
Iversen; Hoever, Wilmot, McNally, Stevens; Laurent, Thompson; Manhoef, Cundle, Bae; Campbell
We say: Southampton 3-1 Stoke City
Stoke will be confident of causing an upset on the back of Southampton's defeat at Leicester. However, the Saints have performed far more consistently on home turf, leading us to predict a fairly-dominant victory for Martin's side.