Vassell, whose penalty miss against Portugal ultimately cost England their place in the European Championships, put Villa ahead after just 11 minutes.
He then turned provider his new strike partner, Carlton Cole, who marked his debut after his arrival in a season long loan move from Chelsea with a smartly taken 33rd minute strike.
Southampton were never really in contention and they were not helped by the fact that their England international striker James Beattie, who was the target of an unsuccessful £6million bid from Villa, was missing with a thigh strain.
But it was at the back that they were really exposed as they simply had no answer to the pace of Vassell and Cole.
Paul Sturrock's side would have crashed to an even heavier defeat if it had not been for the form of goalkeeper Antti Niemi.
The Finnish international starred for the Saints as a pacy Villa side tore apart the harassed Southampton defence.
Villa should been well in control even before Vassell broke the deadlock.
Gareth Barry blazed over the bar from 12 yards after just three minutes before Cole was denied by a fine save from Niemi four minutes later.
But Niemi was powerless to prevent Villa deservedly breaking the deadlock in the 11th minute.
A neat move saw JLloyd Samuel find Barry and his cross was fired goalwards by Lee Hendrie. While a packed Southampton defence was able to deal with Hendrie's shot, they could not prevent Vassell forcing home the rebound.
Southampton were then indebted to Niemi for keeping them in the game when he pulled off another smart save to deny Peter Whittingham after 24 minutes.
Whittingham raced into the area after being released by Samuel and only had Niemi to beat.
But spread himself well and turned Whittingham's powerful drive away for a corner.
The failure to make the most of the chances they created could have proved costly for Villa as Southampton were inches away from equalising in their first real attack in the 28th minute.
Villa goalkeeper Thomas Sorensen managed to block a cross from Brett Ormerod but in the process deflected the ball into the path of Mikael Nilsson who was presented with a golden chance to mark his debut following his £500,000 move from Halmstatds with a goal.
But Sorensen somehow managed to smother the ball on the line before Mark Delaney cleared.
It was a vital intervention by Sorensen as Villa put the game out of the reach of Southampton just five minutes later.
Once again Southampton were torn apart by the sheer pace of Villa's attack that threatens to terrorise Premiership defences this season.
Vassell fed Cole and he surged towards Niemi before rifling home an unstoppable drive from 16 yards that left the Southampton goalkeeper rooted to his line.
That was a blow from which Southampton never recovered, but they did at least step up a gear in the second half after a half-time roasting from Sturrock and the introduction of Rory Delap and Anders Svensson.
Delap and Svensson gave Southampton much more a physical presence in midfield and it was no surprise that the supply lines to the Villa forwards were not as good as they had been in the first-half.
Fabrice Fernandes fired narrowly wide just 60 seconds after the re-start as Southampton sought to find a way back into the game.
Then Kevin Phillips, who needs one more goal to reach 150 for his career, briefly tested Sorensen.
The former England international marksman fired in a low 20-yard drive in the 51st minute that Sorensen did well to push away for a corner.
But Villa were really in cruise control for the remainder of the game.
Thomas Hitzlsperger came closest to increasing their advantage when his 58th minute free-kick from 20 yards was just inches wide of Niemi's near post.
Cole and Vassell also went close to adding to their goals tally as Southampton's dismal opening day form continued.
They have now won just once on the opening day of the season in 13 years.
Man of the Match: Darius Vassell - The England forward made up for his summer heartache by scoring one and making the other as Villa made an excellent start to the new season.