Vakhtang Salia's terrific finish fired Newcastle's second-string into an early lead at Whitley Park but the hosts, despite a dominant start, found themselves on level terms before the break following Reiss Elliott-Parris' strike.
Newcastle, however, were left empty-handed as quick-fire second half efforts, courtesy of Alfie Dorrington and Tyrese Hall, proved the difference on Tyneside.
Under-21s Lead Coach Robbie Stockdale made four changes from last week's National League Cup clash against Tamworth as Mason Miley, Dylan Charlton, Salia and Rory Finneran, the latter captaining the hosts, were all named in the starting 11.
Newcastle's second-string almost took the lead inside the opening 60 seconds as Sean Neave, who netted ten Premier League 2 goals last season, latched onto Finneran's wonderfully weighted pass in-behind the Spurs defence but the 19-year-old forward's first-time effort was blocked over the bar by Tottenham goalkeeper Samual Archer.
The hosts' bright start was rewarded as Salia opened the scoring in the eighth minute. The Georgian striker, who celebrates his 19th birthday on Sunday, controlled Trevan Sanusi's neat pass on the edge of the box before firing a clinical low effort into the bottom left-hand corner.
Newcastle continued their attacking dominance as Neave missed a golden opportunity to double Newcastle's lead. After Sanusi's shot at goal was blocked into Matheos Ferreira's path, the 18-year-old winger fired a first-time pass across the six-yard area but Neave lifted his close-range attempt over the crossbar.
United's youngsters were dealt a blow before the half-hour mark as Sanusi, who made his professional debut for the Magpies in an Emirates FA Cup third round tie against Bromley during the 2024/25 season, was withdrawn due to injury.
Newcastle maintained their one-goal cushion despite the visitors going close to levelling the league clash through Hall as the Jamaica international lashed a low effort wide of the right-hand post.
Magpies goalkeeper George Mair, making his Premier League 2 bow, produced an excellent one-handed save to deny Harry Byrne from equalising, getting across to push away the midfielder's bending effort before the England U17 international held Damola Ajayi's powerful strike minutes later.
The 16-year-old shot-stopper's hopes of a clean sheet were dashed in the 36th minute as Spurs levelled the scoring through Elliott-Parris as the Spurs frontman latched onto Ellis Lehane's pass inside the box before slotting the ball into the bottom right-hand corner.
In the second half, Ferreira was unable to restore Newcastle's lead as the Ashington-born winger, who made his senior debut for his boyhood club in last month's pre-season friendly against Gateshead, raced onto a lofted pass in-behind the Spurs backline but his resulting effort was held by Archer.
Newcastle suffered a tough blow in the 67th minute as Dorrington scored for the visitors. After the Magpies defence were unable to deal with a short corner, the ball eventually fell into the defender's path before his deflected effort dropped into the right-hand corner.
Michael Mills, introduced at the restart in place of Neave, went close to drawing Newcastle level as the Manchester-born winger, a representative of England at U17 level, collected Afner Cá's pass before firing a low effort wide from the edge of the penalty area.
Newcastle's youngsters were immediately punished as Hall extended Spurs' lead in the 71st minute, controlling a pass inside the box before curling the ball into the top right-hand corner.
Newcastle United Under-21s: George Mair, Mason Miley, Dylan Charlton, Miodrag Pivaš (Luke Craggs 46), Henry Johnson, Scott Bailey, Matheos Ferreira, Rory Finneran (c) (Fraser Harper 85), Vakhtang Salia (Afner Cá 68), Sean Neave (Michael Mills 46), Trevan Sanusi (Park Seung-soo 24).