At a time when the Saints sit in 18th position in the Premier League standings, Sheffield Wednesday occupy third spot in the League One table.
Match preview
On the back of Sunday's 4-1 reverse at home to Newcastle United, it quickly became apparent that Ralph Hasenhuttl was at risk of losing his role at St Mary's.
The Austrian's exit was confirmed on Monday morning, and it now appears likely that Luton Town boss Nathan Jones will be appointed as the replacement later this week.
Despite those developments, first-team coach Ruben Selles is expected to take charge on Wednesday, tasked with trying to end a run of two successive defeats.
Before that unwanted run, Southampton had collected five points from three games, but they now sit in the relegation zone and just two points above bottom-placed Nottingham Forest.
The South-coast outfit also possess the worst home record in the Premier League, something which will only offer encouragement to Sheffield Wednesday.
Darren Moore's side are unbeaten in seven matches in all competitions and have lost just once in 10 outings, that setback coming away at League One leaders Plymouth Argyle.
The Owls sit just three points adrift of the automatic promotion places, while they booked their place in the second round of the FA Cup with a 2-0 win over Morecambe at the weekend.
Moore will be encouraged by his side's first clean sheet in four attempts, and Southampton will take note that the Yorkshire giants have conceded just five times in eight away league fixtures this campaign.
Wednesday have reached this stage of the competitions with victories over Sunderland and Rochdale, while Southampton breezed past Cambridge United on away territory.
Southampton EFL Cup form:
W
Southampton form (all competitions):
L
D
W
D
L
L
Sheffield Wednesday EFL Cup form:
W
W
Sheffield Wednesday form (all competitions):
W
W
D
D
W
W
Team News
Southampton will be without Juan Larios after he was withdrawn during the first half against Newcastle, and further alterations are expected to be made.
James Ward-Prowse is in line to be handed a rest, while the Saints are unlikely to take any risks on Armel Bella-Kotchap after his recent return from a dislocated shoulder.
Lyanco, Duje Caleta-Car, Ibrahima Diallo, Samuel Edozie and Sekou Mara will all hope to be handed opportunities.
Although Moore is expected to name a strong side, the Wednesday boss will still make a number of changes with Barry Bannan in line for a recall.
Michael Ihiekwe and Marvin Johnson could return to the backline, but Alex Mighten is cup-tied after already representing parent club Nottingham Forest.
Southampton possible starting lineup:
McCarthy; Lyanco, Caleta-Car, Salisu, Perraud; Diallo, Maitland-Niles, Edozie, Adams, A.Armstrong; Mara
Sheffield Wednesday possible starting lineup:
Stockdale; Palmer, Iorfa, Ihiekwe, Johnson; Vaulks, Bannan, Dele-Bashiru; Wilks, Smith, Paterson
We say: Southampton 2-1 Sheffield Wednesday
Given the uncertainty at the Saints, Wednesday will fancy their chances of causing the upset. Nevertheless Southampton have plenty of prospects wanting to make an impression, leading us to predict a narrow home victory.