Saints were unable to find sanctuary from their Premier League woes in the Capital One Cup with manager Nigel Adkins coming under more pressure after a disappointing 3-0 loss at Leeds.
Adkins made 11 changes but still fielded a senior team.
However, Saints were outclassed by Championship side Leeds with the manner of the defeat as much as the result shining the spotlight firmly on Adkins and his future once again.
Saints have found life tough since leaving the likes of Leeds behind in the Championship in the summer, accruing just four points from a possible 27, and even the bounty of a quarter-final berth could not chivvy them up tonight as goals from Michael Tonge and El-Hadji Diouf, as well as Luciano Becchio's penalty, saw the home side through.
The tinkering was reflected in Southampton's performance, with the Saints outplayed by their hosts.
It took until the 70th minute for them to register a shot at goal and it will be Leeds, third-round conquerors of Everton, who enter the hat tomorrow night for a first quarter-final appearance since 1996 - a year they made the final.
Such an outcome had seemed likely from the moment the teams were named.
With such an array of changes made, Southampton were unlikely to start the better of the two and so it proved, with Leeds and in particular rookie full-back Sam Byram making the early running.
It took until the 15th minute for the home side to fashion a chance of note, though, and when they did, it resulted in what will surely be considered as one of the worst misses in recent memory.
Aidy White stood up a perfect back-post cross to Diouf and, when he sidefooted across the goalmouth with keeper Kelvin Davis stranded, all Luke Varney had to do was score from a yard, but the former Portsmouth man inexplicably hit wide with Diouf unable to ram home the loose ball.
It was a miss which would often strangle the confidence of a player but seven minutes later Varney was running at the Southampton defence, cutting in and fizzing a drive across goal that crept narrowly wide.
He went even closer as the half-hour mark approached too, beating Davis to Danny Butterfield's poor backpass and, after bravely getting to the ball first, saw his edge-of-the-box effort hit the underside of the bar and fall just away from the onrushing Diouf.
Whether it was owing to unfamiliarity or not, Southampton were well off the pace and their goal continued to lead a charmed life when Rodolph Austin put a free header wide but, in the 35th minute, Leeds got what they deserved when Tonge opened the scoring.
Again Varney was involved, this time with a strong run down the left. His cross was hacked away by Jos Hooiveld but Tonge was lurking and from 16 yards slammed a drive through a crowded box for his third goal of the season.
He would have had a second before the break had Davis not tipped his vicious free-kick over but, despite being fortunate to be just a goal behind at the changeover, Saints came out in a similarly lethargic manner.
As has been the case in the league their defending left a lot to be desired, and had Diouf and then Tonge found their range better after Varney was twice brought down on the edge of the box, they could have been cut adrift.
That applied again in the 64th minute when Varney and Tonge played a one-two, with the former denied by Davis who spread himself well, before in the 70th minute, debutant Emmanuel Mayuka registered Southampton's first effort with a wayward shot.
It got little better than that for Adkins' men, though, and with three minutes left, Diouf wrapped things up.
The goal owed everything to Austin, whose 50-yard run may have included some good fortune, but when his low shot was parried by Davis, Diouf had the easiest of finishes from two yards.
After that there was still time for Leeds to get another in injury time, with Becchio, on as a sub, scoring with his first touch from the spot after Dan Seaborne pulled Tonge down in the box.