An intercepted Jordan Richardson back-pass gifted the Saints the opening goal before Ryan Williams conceded a clumsy penalty which made it 2-0.
The Potters did get a goal back through Karim Rossi, but Jonathan Forte made sure of the three points for the Saints ten minutes from time.
Stoke made three changes from last weekend's 4-1 defeat against Tottenham Hotspur with Immanuel Parry and Ryan Williams replacing Ben Glasgow and Diego Arismendi, while Karim Rossi came in for Mamady Sidibe after the striker was loaned out to Championship club Sheffield Wednesday this week on a one month deal.
The visitors included Forte in their starting eleven while regular first-team centre-back Jack Stephens was also recalled to the team after missing Southampton's last match because he was away on international duty with England Under-18s.
City had the first effort on goal three minutes in, but Rossi's shot from the edge of the box went wide of the post. Southampton 'keeper Cody Cropper played a short pass from the resulting goal-kick which Richardson did well to read. The midfielder stole the ball from the defender and let rip from 30-yards, but his effort went harmlessly over the bar.
The Potters started the better side and were dominating possession, but it was Southampton who took the lead nine minutes in with their first shot of the game. Richardson attempted a backpass to his 'keeper, but a lapse in concentration saw him give it straight to Saints striker Sam Hoskins who, with just the keeper to beat, side-footed the ball into the bottom-right corner for his seventh of the season to break the deadlock against the run of play.
The home side nearly hit back immediately when James Alabi weighted a perfect through-pass for Rossi to run on to and his first time shot was well-saved by the oncoming Cropper in the Southampton goal. The Saints were next to go close when Hoskins' low cross found Tadanari Lee in the area, but his snapshot was well blocked by Ben Heneghan.
Southampton's midfield soon started to dictate play and they doubled their lead 19 minutes in, courtesy of another City mistake. Lee turned in the penalty area and tumbled to the ground following Williams' clumsy challenge which left the referee with no choice but to point to the spot. The Japanese international got up to take the spot-kick and coolly hit it down the middle of the goal after Potters 'keeper Daniel Bachmann dived to his left.
By this point, the Saints had only ventured into the Stoke box four times, but had scored on two of those occasions, and another mistake nearly led to a third. Bachmann came out of his area to clear the ball, but he sliced his kick which went straight to Hoskins. The striker tried his luck from 35-yards but left-back Michael Clarkson slid in to keep it out on the line.
Stoke got a goal back on 25 minutes when a long ball evaded two Saints defenders and found captain Jordan Keane on the right flank. The defender's volleyed cross found an unmarked Rossi whose low header beat the 'keeper for his first goal of the season and put Stoke back in it.
Lee had a chance to restore the visitors' two-goal advantage shortly after. Ben Reeves played in the Japanese striker who beat the offside trap to go one-on-one with the 'keeper, but his shot went wide of the target. Another mistake from Stoke nearly led to another goal as Bachmann fluffed his goal-kick which went straight to Lee who fed Fonte, but Stoke's keeper atoned for his error.
The visitors were well on top just before the break and continued that trend after half-time with Reeves volleying just wide. Lee came close again on 52 minutes when he beat the keeper to a lofted ball and his header was going in until Heneghan cleared off the line. The centre-back was again on hand to clear another effort off the line 20 minutes later, this time a shot from the lively Hoskins.
Stoke showed very little in the second period and their first good chance of the half didn't come until 75 minutes in, Andy Musungu's drive from the left wing forcing a save from the keeper. But the Saints made sure the three points were going back south with them after 79 minutes. A good passing move on the right wing led to Reeves being played in and his low cross across goal was tapped in by a grateful Forte at the back post.
Stoke had a chance to get one back five minutes from time, but Rossi could only head Musungu's deep cross over the bar and Southampton held out for the win.
Stoke City: Bachmann; Keane (c), Clarkson, Parry, Heneghan; Dawson, Williams (Thomas 63), Richardson; Musungu, Rossi, Alabi.
Southampton: Cropper; Young, Targett, Stephens, Turnbull; Curtis, Hoskins, Moore, Reeves (c), Forte; Lee.