David McGoldrick's superb individual strike completed Southampton's comeback from two goals down to earn the points.
Billy Jones' left-foot effort and Stephen Elliott's fine angled strike put North End in control at half-time.
On-loan Reading defender Alex Pearce's header threw Southampton a lifeline, and Andrew Surman headed them level from substitute Oscar Gobern's cross.
McGoldrick ended a silky run in the final minute with a composed finish to earn Saints a first win in six games.
Preston manager Alan Irvine: "I'm extremely unhappy. We let a game which was completely in our control go away from us.
"We have turned a victory into a defeat in a totally unacceptable manner. The word that springs to mind at the moment is unprofessional. I felt we got careless.
"At half-time I used words like professional, cold, clinical and ruthless. We didn't display those qualities and if you get careless and unprofessional you lose games."
Southampton boss Jan Poortvliet: "For me, the result is a big compliment for the side. When you are 2-0 down it looks bad.
"I didn't think we played bad but in the first half we were playing with no determination, no real drive to win the game.
"I said something at half-time, I was a little bit angry. But I'm very proud of the boys. Sometimes you need luck for a first goal. You need to be there quickly. Then you go on and hope."
Preston: Lonergan, St. Ledger, Mawene, Wayne Brown, McEveley, Nicholson (Sedgwick 76), Jones, McKenna, Wallace, Parkin (Chris Brown 72), Elliott (Mellor 73). Subs Not Used: Neal, Jarrett.
Goals: Jones 36, Elliott 42.
Southampton: Davis, Cork, Lancashire, Pearce, Skacel, Thomson (Gillett 83), Schneiderlin, Surman, Smith (Gobern 46), James (Wright-Phillips 46), McGoldrick. Subs Not Used: Bialkowski, Wotton.
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