Fabian Schär had put the Magpies ahead with a low free kick, but the hosts responded with efforts from Ben Davies, Matt Doherty, Son Hueng-Min, Emerson Royal and Steven Bergwijn to boost their bid for a top-four finish - while United still have work to do to secure their Premier League status.
Eddie Howe made three changes to the starting XI beaten at Everton in Newcastle's last game more than a fortnight ago, with Allan Saint-Maximin, Jonjo Shelvey and Javier Manquillo replacing Bruno Guimarães, Miguel Almirón and Emil Krafth, who had all been on international duty in the days building up to the fixture.
United made a bright start, with Joe Willock seeing a shot superbly blocked by Cristian Romero before Spurs began to dominate proceedings, with Harry Kane dragging an effort wide from the edge of the box, Son testing Martin Dúbravka and Pierre-Emile Højbjerg heading over.
But in the 39th minute, Willock was fouled by Son and Schär stepped up to drill the ball beyond Hugo Lloris for his second goal of the campaign, much to the delight of the 3,000 travelling supporters.
The lead was short-lived, though, as just four minutes later, Son crossed from the left for Davies to equalise from close range - and two minutes into the second half, Doherty stooped to head past Dúbravka from Kane's right-wing delivery.
Chris Wood nearly responded immediately, but shot just wide after bringing a long pass from Shelvey down on his chest, and Son made it 3-1 in the 54th minute after an incisive Spurs move.
A Matt Targett cross was almost turned into his own net by Davies before Brazilian defender Royal made it four shortly past the hour mark, stabbing home from close range after good work from Doherty.
Then, after Willock had headed over from substitute Guimarães' delivery, Bergwijn got a fifth in the 83rd minute for the clinical home side, who climbed above rivals Arsenal in fourth place with the three points.
And while the Magpies' previous two defeats had been narrow and arguably undeserved, there could be no United complaints about this one after their uncharacteristic second-half collapse.
