Adama Traore scored his first goal of the season in injury time to end Southampton's late challenge and earn Wolves their third win in four Premier League games.
The home side looked comfortable after Raul Jimenez and captain Conor Coady put them in control.
Jimenez scored his first goal since November from the spot, after Rayan Ait-Nouri was brought down by Jan Bednarek.
Coady headed in from close range for his second goal of the season after Fraser Forster's positional error.
James Ward-Prowse's stunning free-kick set up a tense finale at Molineux, before Traore made sure of the points with a calm finish late on.