The Saints eliminated Everton on penalties to progress to the last 16 of this season's tournament, while their Championship foes were also triumphant from 12 yards against Fleetwood Town.
Match preview
Offering Southampton a small slice of solace in an otherwise miserable 2024-25 campaign so far, the EFL Cup has provided Russell Martin's men with two morale-boosting successes, firstly a 5-3 thriller versus Cardiff City before a memorable night at Goodison.
After Taylor Harwood-Bellis's header cancelled out Abdoulaye Doucoure's own aerial effort, the former was one of six Saints player to register from the spot, before Alex McCarthy pulled the rabbit out of the hat by saving from fellow veteran Ashley Young.
The upshot of that shootout success is that Tuesday's hosts have now reached the EFL Cup last 16 in three of the last four seasons, but three of their last four appearances at this stage have ended in defeat, the aberration being their run to the semi-finals in 2022-23.
While Martin's men managed to conquer top-flight opposition in the previous EFL Cup round, the Saints' Premier League win counter still stands at zero after nine gameweeks this season, as an early Erling Haaland goal condemned them to a 1-0 loss at champions Manchester City on Saturday.
The Southampton manager - who retains the backing of the powers-that-be for the time being - could certainly pat himself and his players on the back for their plucky performance at the Etihad, but it is now four defeats on the spin for the Championship playoff winners ahead of Tuesday's knockout tie.
Also revelling in their own penalty-shootout prowess in the third round of the EFL Cup, upcoming visitors Stoke City were minutes away from getting the job done in normal time against Fleetwood Town, only for the League Two side to level the score right at the death.
Neither side had brought their shooting boots to Staffordshire, with only three penalties from nine finding the back of the net between them, but the Potters crucially notched two of the successful efforts as Viktor Johansson came up with a pivotal double save.
A fourth-round appearance means that Stoke have already achieved their best EFL Cup run since the 2021-22 campaign - when Brentford ended their journey at this stage - but Championship matters have not gone so swimmingly for Narcis Pelach's team.
Indeed, Stoke only have the one win to show from their last seven matches in the second tier and were beaten 2-0 by Sheffield United at the weekend, a result that ended a four-match unbeaten run for the 2010-11 FA Cup runners-up.
Nineteenth in the Championship standings and just one point clear of the dreaded drop zone, Stoke can at least draw some inspiration from their recent record against Southampton, as April's 1-0 win at St Mary's made it three triumphs from their last five meetings with their South Coast counterparts.
Southampton EFL Cup form:
W
W
Southampton form (all competitions):
W
D
L
L
L
L
Stoke City EFL Cup form:
W
W
W
Stoke City form (all competitions):
L
W
D
D
D
L
Team News
Perhaps the most notable piece of Southampton team news comes from the dugout rather than the pitch, as head coach Martin will be forced to serve a touchline ban on Tuesday after picking up a milestone booking in the loss to Man City.
As one Saint sits on the sinners' step, another one leaves, as Ryan Fraser is eligible to play again following his red card in the recent loss to Leicester City and is certainly a candidate to start this one.
Gavin Bazunu (Achilles), Ross Stewart (calf) and Will Smallbone (thigh) are all unavailable, though, while a check will also need to be made on Flynn Downes, who suffered a knock late on at the Etihad.
As far as Stoke are concerned, none of Sam Gallagher (calf), Bosun Lawal (back), Lynden Gooch (ligament) and Ben Pearson (hamstring) should be back from their respective problems on Tuesday, but each member of the quartet is on track to return at some point in November.
Pelach made one half-time switch in the loss at Bramall Lane on Saturday, swapping out Tom Cannon for Bae Jun-ho up front, although that was seemingly a tactical change from the Potters head coach.
Bae, Niall Ennis and Emre Tezgel are all alternatives to Leicester City-owned Cannon in the final third, but the latter is still Stoke's top scorer this term with four strikes and ought to reprise his role against Premier League opposition.
Southampton possible starting lineup:
McCarthy; Bree, Wood, Harwood-Bellis, Taylor; Ugochukwu, Aribo; Cornet, Lallana, Fraser; Armstrong
Stoke City possible starting lineup:
Johansson; Tchamadeu, Gibson, Phillips, Rose, Bocat; Manhoef, Burger, Thompson, Koumas; Cannon
We say: Southampton 2-0 Stoke City
Stoke's failure to make the net bulge against Sheffield United made it four road games without a goal for the Potters, and that streak should become five for a side who often fail to bring their shooting boots with them to away days.