First-half goals by Brett Ormerod and Kevin Phillips helped Southampton send Leeds to the foot of the Premiership.
After Fitz Hall hit the bar with a header early on, David Prutton fed Ormerod to fire past Paul Robinson.
Phillips then took advantage of a Zoumana Camara mistake to double the Saints' lead before half-time.
Defender Matthew Kilgallon headed his first senior goal from Ian Harte's cross to give Leeds hope - but they were unable to find an equaliser.
The game kicked off with Leeds already propping up the table after Wolves' win over Manchester United - while Saints left top scorer James Beattie on the substitutes' bench.
Home keeper Antti Niemi was called into action early on when he came out well to dive at the feet of Eirik Bakke.
However, Saints went close at the other end when Rory Delap's long throw found advancing centre-back Hall, who rose unchallenged to crash a header against the woodwork.
36 mins: Ormerod gives Saints the lead
43 mins: Camara's mistake sees Phillips make it 2-0
75 mins: Kilgallon gets one back for Leeds
Danny Higginbotham then headed wide from close range when Robinson hesitated to claim a corner, while Zoumana Camara earned himself a booking after bringing down the lively Anders Svensson.
But while Robinson had done well to palm away a 30-yard Svensson effort, he was eventually beaten just under 10 minutes before the interval when Ormerod ran onto a clever pass from David Prutton to drive the ball past Robinson.
Camara's afternoon got worse when he miscontrolled the ball and was robbed by Phillips, who sped through to claim his first goal since August.
Leeds had little to offer in return, although Alan Smith tested Niemi from the edge of the area soon after the interval, and the Finn made hard work of smothering Smith's low shot.
The home side, searching for their first victory in six games, enjoyed plenty of possession but with 15 minutes remaining, Kilgallon reduced the deficit when he met Harte's left-wing centre with a glancing header.
Phillips then wasted a chance to make it 3-1, shooting himself as Ormerod was left waiting for a pass that never came.
Robinson even joined the attack for a late free-kick, but it was to no avail as Eddie Gray's side faced up to their fifth successive defeat.
Southampton: Niemi, Dodd, Hall (Kenton 80), Michael Svensson,
Higginbotham, Fernandes (Telfer 85), Anders Svensson, Delap,
Prutton, Ormerod, Phillips (Beattie 86).
Subs not used: Blayney, Pahars.
Booked: Anders Svensson.
Leeds: Robinson, Kelly, Camara, Kilgallon, Harte, Pennant,
Morris (Bridges 65), Bakke, Seth Johnson, Milner, Smith.
Subs not used: Carson, Roque Junior, Barmby, Richardson.
Referee: A Wiley (Staffordshire).