The Saints' Darrel Powell put through his own net following a goalmouth scramble to give the Potters the lead.
Headers by Ryan Shawcross and Mamady Sidibe from Liam Lawrence corners made it 3-0 for the hosts at half-time.
Stern John fired home a 20-yard volley straight after the break and slotted in from Andrew Davies' pass but the visitors could not find an equaliser.
Stoke manager Tony Pulis:
"I thought Southampton played really well for 20 minutes then and really, really put us under some pressure.
"But in the last 15 minutes we had the best chances. Leon Cort could have had two and Rory Delap should have scored."
Southampton caretaker manager John Gorman on his side's unsuccessful fightback:
"We showed good character from the start of the second half - all the players were like men, winning the tackles and the second balls.
"We played magnificently, it was a wonderful effort that at the very least deserved a draw."
Stoke: Simonsen, Griffin, Cort, Shawcross, Pugh, Lawrence (Zakuani 87), Delap, Diao, Whelan, Sidibe, Fuller.
Subs Not Used: Hoult, Parkin, Gallagher, Pericard.
Booked: Pugh, Fuller.
Goals: Powell 27 og, Shawcross 35, Sidibe 44.
Southampton: Davis, Davies (Wright-Phillips 80), Powell, Ostlund, Wright, Viafara, Surman, Saganowski, Idiakez (McGoldrick 88), Euell, John.
Subs Not Used: Hammill, Lallana, James.
Booked: Saganowski, Idiakez, Ostlund.
Goals: John 46, 54.
Att: 19,481
Ref: Nigel Miller (Durham).
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