Bradley Wright-Phillips struck late on to keep Southampton's play-off hopes alive and leave Leeds deep in trouble.
Leeds' Alan Thompson saw red after 32 minutes after a clash with John Viafara, which saw angry players being kept apart by referee Tony Bates.
Wright-Phillips broke the deadlock with six minutes left, hooking home a cross from fellow substitute Djamel Belmadi.
Grzegorz Rasiak had the ball in the net after Wright-Phillips' strike, but it was ruled out for offside.
Southampton manager George Burley:
"We knew Leeds would be fighting for their lives and all credit to them, they made it difficult for us to break them down.
"But we kept at them, we put Bradley on the wing to give us some more finishing power and it paid off.
"I think we deserved it."
Leeds boss Dennis Wise on Thompson's sending off
"The linesman made the decision but he was 40 yards away.
"Thompson pulled Viafara away from Eddie Lewis because they were going to clash, and the officials misunderstood.
"I'm always talking about the refs, but they should be penalised."
Southampton: Bialkowski, Baird, Pele, Lundekvam, Surman, Idiakez (Belmadi 65), Guthrie, Viafara (Wright-Phillips 54), Skacel, Rasiak (Best 88), Jones.
Subs Not Used: Davis, Cranie.
Booked: Baird, Lundekvam, Pele.
Goals: Wright-Phillips 84.
Leeds: Ankergren, Richardson, Heath, Rui Marques, Robbie Elliott, Blake (Foxe 38), Kishishev, Thompson, Lewis (Kandol 85), Cresswell, Healy (Armando Sa 65).
Subs Not Used: Stack, Moore.
Sent Off: Thompson (34).
Booked: Rui Marques, Cresswell, Robbie Elliott, Foxe.
Att: 29,012
Ref: T Bates (Staffordshire).