Wales international Vokes took just 39 seconds to put Wolves on the road to a 3-0 victory which re-established their five point lead at the top of the table.
Skipper Jody Craddock doubled Wolves advantage with his first goal of the season in the sixth minute, before a David Jones penalty ended all hopes of a Saints comeback.
Southampton have now gone seven games without a win and, coupled with their off the field problems, their future looks far from bright.
In contrast, Wolves' destiny is now firmly in their own hands with just four games remaining.
Mick McCarthy's side could not have asked for a better start as they forced a quick corner.
Jones delivered a pin-point centre that Vokes met in a crowded goalmouth with a powerful close-range header, to score his eighth goal of the season.
The accuracy of Jones from the right flank was a major problem for the Southampton backline and it was the key to Wolves striking again through Craddock.
Jones picked out the Wolves skipper and Craddock headed from 14 yards.
To their credit, Southampton didn't let their heads drop and they were inches away from grabbing a lifeline after 14 minutes with Marek Saganowski, who scored a hat-trick when the Saints won 6-0 at Molineux two seasons ago, flashed a header just wide.
But unfortunately for Southampton, that was nothing more than a false dawn and their fate was sealed just four minutes later.
Trying to help out in defence, Saganowski sent David Edwards crashing to the ground and referee Anthony Taylor had no hesitation in pointing to the penalty spot.
Jones stepped up to send Kelvin Davis the wrong way from the spot as he helped himself to a fourth goal this term.
Unsurprisingly, Wolves did noticeably ease off after surging into such a commanding lead.
It allowed Southampton to make more off an impact at the start of the second half when Jason Euell and Bradley Wright-Phillips were both sent on.
They did add more menace to the Saints attack and combined to set up Saganowski in the 51st minute, only for the Polish forward to be denied at the near post by a smart save from Wayne Hennessey.
Wright-Phillips then saw his 69th minute shot deflected just wide as Southampton's search for a consolation strike proved to be fruitless.