The hosts were reduced to ten men towards the half-hour mark after Fabian Schär's straight red card, following an altercation with Saints forward Ben Brereton Díaz, but found themselves ahead on the stroke of half-time following Joelinton's composed finish.
After playing with over ten men for over an hour, recording 22 per cent possession throughout the 90 minutes, the Magpies held firm to record an impressive clean sheet along with maximum points at St. James' Park.
Eddie Howe's side were aiming for a third successive opening day win and faced a Southampton side who gained promotion to the English top-flight last term via Championship play-offs.
Southampton defender Jack Stephens looked to have stroked the visitors ahead in the opening stages after tapping home from Will Smallbone's cross-cum shot but the Saints skipper's effort was disallowed after straying into an offside position.
The contest took a dramatic twist towards the half-hour mark as Schär was sent off for United. After Brereton Díaz shoved the Swiss defender to the ground, the latter appeared to push his head into the Chile international, who theatrically fell to the floor, before referee Craig Pawson gave the centre-back his marching orders to the frustration of the home supporters.
Brereton Díaz, heavily booed by the majority of the 52,196 fans in attendance, almost fired the Saints ahead after connecting with Yukinari Sugawara's bending cross from the right flank but directed his header wide of the target.
In the 45th minute, Newcastle took the lead through Joelinton's strike. After Alexander Isak pounced upon Alex McCarthy's weak pass inside the box, the Swedish striker picked out Joelinton before the Brazilian midfielder, who celebrated his 28th birthday on Wednesday, slotted a low effort into the left-hand corner in front of a raucous Gallowgate End.
Lewis Hall produced a heroic goal-line clearance shortly after the restart to prevent Adam Armstrong equalising for the visitors, hooking away the former Magpies forward's low first-time shot from Joe Aribo's dangerous cross before Brereton Díaz's rebound was crucially blocked out for a corner by Livramento.
Pope, making his first Premier League outing of the calendar year on home soil since sustaining a dislocated shoulder against Manchester United in December, produced an excellent save to deny Armstrong as the Geordie forward's stinging drive was importantly tipped over the crossbar by the England international.
Newcastle continued to defend valiantly throughout the second-half although Armstrong went close once more to dashing United's clean sheet hopes as the striker's deflected effort from Flynn Downes' tee-up flew narrowly wide of the left-hand post.
With the full-time whistle approaching, Pope contributed with a key save as the Magpies shot-stopper held Carlos Alcaraz's goalbound header from Sam Amo-Ameyaw's teasing cross into the box.
Despite five minutes of stoppage-time, Newcastle were able to withstand Saints' late attacking surge to secure a valuable three points.
Newcastle United: Nick Pope, Tino Livramento, Fabian Schär, Dan Burn, Lewis Hall (Lloyd Kelly 70), Sean Longstaff, Bruno Guimarães (c), Joelinton, Jacob Murphy (Emil Krafth 30), Anthony Gordon (Harvey Barnes 70), Alexander Isak.
Subs not used: Martin Dúbravka, Kieran Trippier, Matt Targett, Joe Willock, Miguel Almirón, Will Osula.
