The Magpies were trailing to the league's bottom club when the England forward, who had scored twice against Everton three days earlier, was introduced at half time - but Eddie Howe's men ended the afternoon with a 3-1 victory which kept them in third place despite Manchester United edging past Aston Villa at Old Trafford.
And Wilson, United's leading marksman for the past two terms, is now enjoying his best ever scoring season in the top flight with 15 and counting in an increasingly memorable campaign for both him and his club.
The relegation-threatened visitors had a couple of early chances, with Kyle Walker-Peters and Stuart Armstrong seeing shots comfortably dealt with by Nick Pope either side of a seventh-minute Anthony Gordon effort which hit the side-netting after the former Everton man had been played in by Jacob Murphy.
Then, from a Gordon cross, Alexander Isak's header fell to Bruno Guimarães but the Brazilian's volley from just inside the area whistled wide.
Gordon was heavily involved in the first half, and came agonisingly close to his first goal for the Magpies in the 19th minute when Isak sent him through. Gordon, one-on-one with Alex McCarthy, took a shot early but it clipped a post and went behind.
Two minutes later, a deep corner from Kieran Trippier was nodded back across goal by Fabian Schär and Joelinton headed just wide.
There was a lull in proceedings after that, until the 40th minute when Murphy - who had swapped wings with Gordon - cut inside from the left but his right-footed curler was just too high.
And a minute later, United were behind when Romeo Lavia dispossessed Guimarães allowing the Saints to break, and Kamaldeen Sulemana centred from the right for Armstrong to divert into the Gallowgate End net.
Wilson was introduced in place of Gordon at the interval and within two minutes, the England striker met a Trippier free kick but his header was off target.
In the 53rd minute he was denied again; Sven Botman stretched to meet Trippier's free kick, McCarthy saved and Wilson was unable to force the loose ball home.
But seconds later, he had equalised with his 14th of the campaign. Isak made inroads on the left and cut the ball back for Wilson, who adjusted his body to sweep home with the confidence of a man in arguably the form of his life.
Newcastle pushed hard for a second after that, with Murphy wriggling into the box only for Jan Bednarek to block his shot before the same player got in the way of a powerful strike from Joelinton. The resulting corner was only cleared as far as Guimarães, who teed up Willock but his drive was gathered by McCarthy.
Then the Saints keeper tipped a Wilson header over after he was picked out by Willock. In the 74th minute, Wilson thought he'd put United ahead, but his effort was ruled out for offside following a lengthy VAR review.
However the vital second goal did come in the 79th minute, when substitute Theo Walcott inadvertently diverted a Trippier corner into his own net.
Then Wilson made sure of the three points as he seized upon a mistake from Ainsley Maitland-Miles and rounded McCarthy to slot into the empty net.
Guimarães nearly added a fourth after a clever one-two with Joelinton and substitute Elliot Anderson had a shot blocked in added time before Wilson was denied a first hat-trick for the club when his shot hit the bar, then the ball looped up in the air and bounced off the woodwork for a second time on its way back down.
But Newcastle have now scored 13 goals across three matches in the last seven days and maintained their push for a top-four finish with just five games left to play.