Southampton had the first two opportunities after a scrappy start with Jhon Viafara belting his shot over from 12 yards, before Stern John's header was comfortably fielded by Steve Simonsen.
But Stoke's power game gradually took charge and Liam Lawrence cracked a free-kick narrowly wide before the winger's corner led to his side taking a 27th minute lead.
Southampton struggled to clear from a goalmouth scramble and Darren Powell put the ball into his own net with an attempted clearance which struck the post on its way in.
A crowd of close to 20,000, swelled by a free ticket offer for Stoke's home game against Scunthorpe on Friday, were now in full voice and they didn't have to wait long for number two.
Lawrence swung over a 35th minute corner from the right and Ryan Shawcross towered above the statuesque visiting defence to bury his header into the roof of the net.
And Stoke's 44th minute third was almost a carbon copy as another Lawrence flag-kick was met with another unstoppable header, this time from Mamady Sidibe.
It was the striker's first goal of the season in his 25th appearance.
Southampton gained a lifeline just 11 seconds into the second half when John got the better of Shawcross and hammered a 20-yard volley beyond Simonsen.
And it was really game on in the 54th minute after a well worked free-kick between Inigo Idiakez and Jermaine Wright led to John hammering his second.
The Saints were flying and Stoke totally shell-shocked, so much so that the visitors could have scored four more in the next 15 minutes with John remaining in the thick of the action.
But Tony Pulis' side somehow rode the storm and retaliated to go close to a fourth, with Shawcross foiled by Kelvin Davis and Leon Cort heading inches wide as an exhilarating game neared a conclusion.