Saints had not won at Old Trafford since 1988 prior to last weekend's impressive 1-0 win, and Ronald Koeman was to claim a second record this weekend - as Saints overcame the Geordies for the first time since March 1997.
Southampton started the game second best, with Fraser Forster having to be alert in the opening stages to deny Newcastle the opener, first denying Ayoze Pérez before standing firm to catch a vicious effort from Yoan Gouffran.
The first goal of the game came from the first attempt by a Saints shirt, when Eljero Elia capitalised on an inviting through ball from James Ward-Prowse after a knock-down from Graziano Pellè. The on-loan Dutch winger acted quickly to fire a low effort past Tim Krul and make the net bulge as he notched up his first goal for the club.
He made an immediate beeline for Saints boss Ronald Koeman, hugging the former Feyenoord manager in a move he later described as 'a thank-you' to the man who put his trust in Elia and gave him a chance to re-ignite his career.
Newcastle pulled level in the 29th minute, when Yoan Gouffran was the recipient of a huge slice of luck. A ball for the onrushing Frenchman was turned into the net when Romanian defender Florin Gardos went to ground to try and clear the ball, only for it to cannon off of the knee of the Newcastle midfielder and balloon into the back of the Saints net.
The hosts finished the first half on top, as Saints stood firm to deny the Magpies bagging a second goal.
After the break, the game continued in a similar pattern, with Newcastle looking more likely to score - until a double substation by Saints boss Ronald Koeman with 30 minutes remaining changed the course of the match.
Jack Cork replaced James Ward-Prowse and immediately established a vice-like grip on the centre of the field, while Shane Long's direct runs caused a whole host of problems for Newcastle after he replaced Dušan Tadić.
Just two minutes after the substitutions, Eljero Elia bagged his second of the afternoon, rushing on to a flick on from Shane Long before poking past Tim Krul with the help of a deflection. Elia celebrated his second by recreating an iconic goal celebration from Cristiano Ronaldo, flying into the air before standing and posing with the name on the back of his shirt showing to the crowd as he once again sent the Saints fans into raptures.
Newcastle had chances. Massadio Haidara picked out Moussa Sissoko, but the French midfielder's header flew harmlessly wide of Forster's goal. Jack Colback's corner was turned towards goal by Paul Dummett, but fortunately for Saints his effort failed to trouble Forster.
Graziano Pellè could've secured a third goal for Saints when he rose to smash a header back off the bar after meeting Nathaniel Clyne's inch-perfect cross.
Thankfully, despite a late barrage of corners, Saints stood firm - even if José Fonte was fortunate to get away with a late and clear, but unintentional, handball in the penalty area.
The win means that Ronald Koeman's men remain third, with Champions League rivals Arsenal set to face Manchester City tomorrow.