Danny Ings continued his hot streak in front of goal just after the interval after he was allowed clean through on goal before slotting home.
That was before Newcastle United's stand-in captain Jonjo Shelvey made it three goals in as many games when he rose to meet an Andy Carroll cross mid-way through the second half.
Federico Fernandez was on hand to finish after a Sean Longstaff shot was parried just four minutes from time to give the Magpies another crucial three points.
First half struggles
Newcastle started in sluggish fashion and couldn't get close enough to their Southampton opposition, who were taking early control of the midfield.
They should have been in front too when on 20 minutes a mis-placed Jetro Willems pass was intercepted by Nathan Redmond who only had Martin Dubravka to beat, but the shot was well saved.
The Saints, fresh from two consecutive victories over Watford and Norwich City, were looking the more dangerous side.
The hosts slowly began to find their feet, and on 29 minutes a promising darting run from Allan Saint-Maximin almost resulted in a chance for Joelinton, but it ricochaed off the Brazilian to safety.
Half time rotation
Steve Bruce turned to Fabian Schar from the bench at the break after Ciaran Clark seemed to pay the price for three matches in eight days, but wasn't an ideal start from the Swiss international.
It was six minutes into the second half when a long ball forward was left by Schar, and Ings got the better of Fernandez before calmly slotting the ball beyond Dubravka.
It was certainly a deserved lead and Bruce didn't hesitate to alter things, introducing Carroll for Joelinton just before the hour mark.
It took just six minutes for Carroll to make his mark when Newcastle grabbed their equaliser.
The big centre forward played provider when he swung in a delightful cross for Jonjo Shelvey to meet in the box to guide a header past Alex McCarthy.
The equaliser from Shelvey arguably came from nowhere, but the home side were buoyed by the boost it gave the crowd, but Southampton came back.
Schar and Paul Dummett both had to be brave and both required treatment when involved in two separate Southampton set-pieces, to keep the score at 1-1.
The game was becoming stretched and the physical presecen of Andy Carroll changed the whole complexion for United, allowing his teammates to feed off his aerial dominance.
United's late push was rewarded when a long shot from Longstaff could only be parried by McCarthy, and on hand was the unlikely Fernandez to score his second goal of the season.
Harsh on Saints
It was a tough one to take for Ralph Hasenhuttl and his side who for large parts were the better team and they look a vastly-improved team from the one which conceded nine goals at home to Leicester City in October.
It was a performance to take spirit from, but on the other hand for Newcastle it was a three points that signifies a team on the up, winning when not playing so well.
It wasn't just Clark who fell to injury, as Saint-Maximin left the ground on crutches after clutching his hamstring late on which has come at a cost of United's second win in four days.
Next for Newcastle is Burnley on Saturday whilst the Saints host West Ham United.