A sensational strike from the Senegalese forward helped the Magpies to a convincing victory despite Morgan Schneiderlin's early goal and Rickie Lambert's 100th for the Saints
The visitors had taken an early lead through Morgan Schneiderlin before Moussa Sissoko equalised and Papiss Cisse scored a sensational 35-yard volley to give the Magpies a half-time lead.
The Saints responded through Rickie Lambert's 100th goal for the club straight after the restart but a Yohan Cabaye penalty and Jos Hooiveld's own goal sealed victory to give the hosts their third win in four league games.
Newcastle were without first-choice goalkeeper Tim Krul, though Cheikh Tiote returned from illness and Mathieu Debuchy, Steven Taylor and Davide Santon were all reinstalled after being rested during Thursday's win over Metalist Kharkiv.
Southampton, meanwhile, were without Guly do Prado but welcomed Luke Shaw back from injury, while skipper Adam Lallana made his first start in two months.
And the visitors made a sensational start as Jack Cork whipped a dangerous cross into Lambert, who nodded down for Schneiderlin to smash home a near-post half-volley after just three minutes.
But on the quarter of an hour mark, the Magpies began to quash Southampton's superiority as Sissoko smashed a low drive across goal to force Artur Boruc into a diving save.
Next to come close for the hosts was Cisse as Yoan Gouffran's mishit shot fell straight to the Senegalese forward, only for him to lose his footing and fire miserably wide from just yards out.
By the half-hour mark, though, the Magpies had taken complete control and Sissoko would soon give them just reward.
On 33 minutes, Gouffran made a fantastic run down the left, twisting and turning all the way to the byline before unleashing a low shot straight at Boruc. The Polish shot stopper was equal to the Frenchman's effort but sent the ball into the path of Sissoko, whose easy tap-in gave him his third league goal.
And 10 minutes later, the home side had the lead thanks to a simply unstoppable strike from Cisse. Stand-in keeper Rob Elliot had thumped a long ball up-field and the 27-year-old – who was a good 35 yards out – took one look at goal and smashed a flawless volley straight into the top corner.
Yet the Saints responded immediately after the break as Lambert went close with an excellent free kick that was matched for its brilliance by Elliot's fingertip save.
The 31-year-old would not be denied at the second time of asking, however, as Lallana sent a ferocious low cross into the area and the forward pounced to score his 100th Southampton goal.
But the home side responded swiftly. Southampton's brief ascendancy was followed by a period of sheer Newcastle pressure and on 66 minutes, the Magpies had their reward with a penalty.
Danny Fox had handled Debuchy's cross in the area and Cabaye became the third Frenchman of the game to score as he calmly slotted the ensuing spot kick past Boruc.
And the Saints' misery was compounded after 79 minutes, when Fox cleared Santon's cross straight into the shins of Hooiveld, with the ball sailing in for the Dutchman's third own goal of the season.