Patrick Bamford scored his 13th goal of the season to help Leeds end a run of back-to-back defeats to extend Southampton's own winless run to a far more worrying eight matches.
The striker struck early in the second half, timing his run to perfection to beat offside and latch on to Tyler Roberts' through-ball before firing a low shot into the far corner.
A neat Stuart Dallas finish from the edge of the box and Raphinha's superb free-kick sealed the points.
Prior to the opener Leeds had been somewhat on the back foot, with Jan Vestegaard and Nathan Tella spurning good early chances for the Saints, who were also aggrieved at two refereeing decisions.