Leeds missed three clear first-half chances and were then made to pay dearly for their own defensive lapses to give Southampton a flattering 2-0 interval lead.
Eddie Gray's side rallied after the break, pulled a goal back and almost equalised with an own goal, narrowly averted when Swedish defender Michael Svensson hit the inside of his own post, before the rebound was cleared off the line.
Leeds were left to regret their failures in attack and none more so than Alan Smith who dragged an 11th minute shot wide with only the keeper to beat before Jermaine Pennant shot against the legs of the keeper in the 33rd.
Southampton were always dangerous and big defender Fitz Hall struck the bar with a header and Paul Robinson made a superb diving save to keep out a goalbound shot from Anders Svensson.
The turning point came in the 36th minute when Brett Ormerod ran through onto a pass from David Prutton and held off Matthew Kilgallon's challenge before firing home his fifth league goal of the season.
Leeds defender Zoumana Camara was booked for a foul in the 23rd minute and it was his error just before the break which gifted Southampton their second.
He failed to control a square pass from Gary Kelly allowing Kevin Phillips to dispossess him and go on to score with a shot which went through the legs of Robinson.
It was Phillips' first league goal since the opening day of the season at Leicester ending a run of 17 matches without a goal, the worst run of an otherwise prolific career.
Leeds faced a huge task pulling back two goals in the second half and it might have been worse as Rory Delap had a header cleared off the line by Kilgallon while Ormerod hit the outside of a post.
Leeds pulled a goal back in the 76th minute when Ian Harte crossed from the right and the unmarked Kilgallon headed in at the near post.
Kilgallon's goal set up a furious finale in which Michael Svensson stumbled in turning a centre from James Milner on to the inside of his own post but somehow Saints held out.
Anders Svensson was booked for a foul in stoppage time and Saints boss Gordon Strachan took off Hall and replaced him with Darren Kenton in a bid to shore up his defence.
Southampton started the match without leading scorer James Beattie who sat on the bench nursing rib and ankle injuries and he came on for the final three minutes to help his side end a run of five matches without a win.
Strachan is backing Phillips to rediscover the form which saw him win the European Golden Boot award while he was with Sunderland.
Phillips netted 30 league goals in his first season in the Premiership but has struggled to recapture his best form for Southampton.
Stand-in Leeds boss Eddie Gray had refused to use Leeds' off-the-field problems as an excuse for his side's slump to the bottom of the table.
Leeds face being plunged into administration if they cannot find a buyer by Monday.
Gray said: "I do not know what the latest is on the financial situation but we will find our soon enough. The chairman is working hard behind the scenes trying to get things sorted out.
"I am sure he is doing his upmost to resolve the situation we are in.
"The player met the PFA last week but we cannot use that as an excuse. I thought we stuck at it and showed a lot of determination particularly in the second half.
"But when you play in the Premiership and you concede the goals we did it is an uphill battle.
"We had a few chances in the first half but when you make the sort of mistakes we did you get punished.
"I think we have the players to get out of trouble but we are in a dire situation.
"We are all disappointed because we have lost another football match but we can take heart from the performance.
"In the situation we are in you have to win games and the matches are running out.
"But I thought we showed more of what we are capable of and in the final 15 minutes could have sneaked a point."
Man-of-the-match: Southampton defender Michael Svensson was a rock in the home defence and his timely tackling and excellent positioning was a major factor in the victory for Gordon Strachan's side.