After Raul Jimenez’s goal difference between the two sides in the reverse game in September, the Mexican striker scored again when he scored a first-half penalty kick from Wolverhampton ahead.
The Saints had plenty of chances of their own but Jose Sa blocked them before Captain Connor Coady stepped up to double his team’s advantage.
Wolves looked to be on the cusp of watching the game before James Ward-Prowse hit a trademark, but sensational, 30-yard free kick to give the visitors hope.
Southampton then hit the crossbar before substitute Adama Traore scored his first goal of the season to give Wolves their third win in a row in all competitions.
Bruno Lage made five changes to the side that enjoyed the FA Cup last week but stuck to a 3-4-3 formation.
Remarkably, young defender Totti Gomez received his first match for Wolverhampton and started to the left of the three defenders. The 22-year-old has spent the last 18 months on loan to Grasshoppers and only arrived at Wolverhampton to train with the team for the first time this month.
He came to replace Fernando Marcal, who knocked out in the first half against Sheffield United, while Roman Sais is absent with Morocco in the African Nations Cup.
Wolves have also taken a beating as Robin Neves and Kei Jana Hoover miss Covid-19.
Ralph Hessenhuttl picked a fixed lineup after his 4-1 midweek win over Brentford and started with a 3-5-2 formation.
However, they have two players back in the squad to bench on Kyle Walker Peters and Jan Valery.
Despite his intense and unexpected entry into the Premier League, Gomez showed no signs of nervousness in the early minutes. Molineux showed his appreciation as he made his first touch, then made a good block to deny Nathan Tella’s cross.
A stampede in the penalty area almost gave Armando Bruga a chance, but goalkeeper Sa grabbed the ball on the second attempt.
It was a quiet start for 15 minutes as neither side created many chances. Southampton had plenty of set pieces and most of the ball, while Wolves struggled to get to their rhythm.
Wolves’ first attack forward almost resulted in a goal, when Rayan Ait-Nouri was fired down the left and a low cross was parried in front of Lyanco’s goal. At the other end, Sa is called into action to deprive Romain Perraud.
Referee Michael Salisbury was the biggest talking point after 20 minutes with some strange decisions and general inconsistency leading to some reactions from the home team’s fans.
The wolves started growing in the game and a superb Leander Dendoncker cross pass was beautifully rounded off by Daniel Podence. He raced forward and cut inside but his shot was saved by Fraser Forster.
Once again, the VAR and officials had their time to shine when Ait Nouri was taken off by Jan Bednarek in the Southampton box. Salisbury originally gave a corner kick, but after a lengthy check using VAR and once the referee reached to check the side screen, a penalty was awarded.
Jimenez rose to calmly score the penalty kick and hit Wolves in front.
But just moments later, Southampton had to equalise. Muhammed Salisu was found in the penalty area from just five yards away but his header was superbly saved by Sa.
In the first half, Saliso met with a corner kick but again Sa saved by flipping it over the ball.
Although the visitors had better chances and had to score, Wolves entered the first half with a 1-0 lead with a penalty kick from Jimenez.
With teams emerging in the second half, Southampton made an offensive switch bringing in Che Adams in place of Ibrahima Diallo. This means that they match Wolverhampton’s 3-4-3 method.
On a slow start to the second half, the first talking point came when Oriol Romeo fell into the penalty area after being caught by Dendoncker. Southampton’s tepid appeals have been waved, but this writer has seen those issued as penalties in the past, so perhaps Wolverhampton got away with it.
Wolverhampton then put the ball into the net through Coady, but it was quickly and correctly disallowed after Gomez, who played Coady on the inside, strayed offside from the free kick.
But moments later, the wolves found their second target. A long free kick came with an own-go by Forster that was met by Max Kellmann and hit the post – but Cody followed it up and finished from close range for the second time of the season.
After the goal the Saints settled and started to see more of the ball as he looked to force them back into the game. A handful of half chances fell by the wayside, including one for Adams, who shot straight at Sa from a tight corner.
With only six minutes of normal time remaining, Ward-Prowse smashed home with a superb 30-yard free kick to give the visitors a lifeline.
Challenges began to arise as the referee Salisbury lost control of the match, but Wolverhampton was battling hard for control of it so they could hold onto their lead.
Perrod almost equalized when a free header hit the back post, before Traore climbed to the other end and missed a great opportunity after Fabio Silva saved Fabio Silva’s efforts.
But moments later Traore was released from the left and, after slipping past Salisu, hit the ball into the bottom corner to give Wolves a break in the six minutes of extra time.
Academy alumnus Luke Cundle came in the final stages of his Premier League debut as Wolves netted a 3-1 victory.
Wolves: Sa, Kilman, Coady, Gomes, Semedo, Dendoncker, Moutinho, Ait-Nouri, Trincao (Traore, 78), Jimenez (Silva, 80), Podence (Cundle, 94).
Unused subs: Rudy, Molden, Sanderson, Giles, Jordaw, Campbell.
Southampton: Forrester, Pendarek, Linko, Salisu, Tella (Armstrong, 71), Ward-Prowse, Romeo, Diallo (Adams, 45), Pero, Redmond, Bruga (Armstrong, 78)
Unused subs: Caballero, Stephens, Walker-Peters, Small, Valery, Long.