With a draw looking odds-on, United boss Joe Kinnear played one final throw of the dice and Duff's crucial strike hoisted the Geordies into unchartered territory this season - 12th position.
The win left Spurs boss Harry Redknapp gutted as he claimed afterwards that the least he had expected was a draw.
Kinnear has now lost only twice in his dozen games in charge on Tyneside and the manager also announced that owner Mike Ashley is to meet Michael Owen's agent in the next three days to discuss details of a new contract.
Newcastle extended their unbeaten run to six games after going ahead through Charles N'Zogbia but it was a lead cancelled out by Luka Modric.
But it was Duff - with his first league goal at St James' Park - who came up trumps as United made it six wins from their last seven Premier League starts over Spurs, including the last four on Tyneside.
Spurs have scored the first goal on just four occasions in their previous 17 Premier League starts and must have feared the worst after falling behind after just 12 minutes.
And Redknapp will have been furious at the way his side were caught flat-footed by a lightning quick Newcastle counter-attack.
Quick thinking from keeper Shay Given paved the way for N'Zogbia, who raced on to the ball which had been launched forward by the keeper.
Benoit Assou-Ekotto was left in a straight challenge with N'Zogbia and, despite appeals for a penalty when they clashed, the Newcastle player was first to get to his feet as he shot beyond Huerelho Gomes.
Newcastle were unable to press home their advantage any further and Spurs drew level after 29 minutes in bizarre fashion.
Michael Dawson just beat Shola Ameobi to a throughball that he hoisted forward and it caught United out.
The back four relaxed knowing Roman Pavlyuchenko was in an offside position but failed to notice Modric charging through and the one-time Newcastle target levelled it up.
That was Ameobi's last taste of the action as he went off with a hamstring injury and was replaced by Mark Viduka.
Both sides created half-chances in the second period, with the only clear-cut opportunity falling to Michael Owen who blazed over from just six yards.
That chance was set up by N'Zogbia who was easily the best player on the park by a country mile.
And it was no coincidence that the little Frenchman was involved in the winner having switched from left midfield to left-back after Jose Enrique limped off to be replaced by Duff.
N'Zogbia's astute ball to Duff saw him bring it under control and work a one-two with Viduka before seizing on to the big Aussie's back-heel and firing under Gomes.