The young Magpies fell behind in the first-half at Whitley Park following Lucá Williams-Barnett's clinical finish before Cathal Heffernan's header, guiding the ball home from Alfie Harrison's free-kick, drew the hosts level before the half-time break.
Williams-Barnett's impressive strike, though, regained Spurs' lead shortly after the restart before quick-fire efforts in the closing stages, courtesy of Dane Scarlett's free-kick and Tynan Thompson's finish, condemned United's youngsters to defeat.
Adam Lawrence made three changes from the side which were held to a 1-1 away draw against Reading as Alex Murphy and Max Thompson, both named on the bench for United's UEFA Champions League victory against Union Saint-Gilloise on Wednesday, featured in the starting eleven while 17-year-old striker Kacey Wooster was handed his full debut at under-21 level, leading the line in place of the suspended Sean Neave.
In blustery conditions on Tyneside, Newcastle almost fell behind inside the opening 60 seconds as Thompson rattled the woodwork for the visitors, latching onto Yusuf Akhamrich's pass inside the penalty area, following a dangerous attack, before drilling a ferocious effort onto the underside of the crossbar.
Wooster, who has scored three goals in his opening three league games at under-18 level, was unable to fire Newcastle ahead as the 17-year-old striker got in behind Spurs' backline following Alex Murphy's lofted pass but, despite cutting inside, saw his deflected attempt held by Tottenham 'keeper Aaron Maguire.
Newcastle conceded in the 20th minute through Williams-Barnett as the 17-year-old attacking midfielder collected the ball on the edge of the penalty area before drilling a powerful low effort into the far right-hand corner.
Thompson, who joined Newcastle's Academy at the age of 11, produced a key stop to prevent Spurs from doubling their lead as Rio Kyerematen raced onto Williams-Barnett's pass before his resulting effort at goal was blocked by the Ponteland-born shot-stopper.
United's youngsters equalised in the 38th minute courtesy of Heffernan as the Irish centre-back, a representative of his country at under-19 level, excellently guided Harrison's inviting free-kick at the back post into the far left-hand corner.
Newcastle went agonisingly close to taking the lead as another teasing set piece from Harrison was headed into the six-yard area by Heffernan before the ball found its way into Rory Finneran's path, who saw a fierce drive blocked out for a corner inside a crowded penalty area.
In the second-half, Thompson recorded a strong stop to deny Scarlett from regaining Spurs' one-goal cushion after the striker was slipped in behind by Williams-Barnett's delicately weighted pass but Thompson stood firm to block the shot at goal before smothering the loose ball.
In the 53rd minute, though, Spurs restored their lead courtesy of Williams-Barnett's impressive finish, picking the ball up on the edge of the box before rifling a powerful strike into the top right-hand corner.
Tottenham struck the woodwork for a second time in the contest shortly after as Kyerematen collected the ball in a dangerous position and, following a surging run towards the penalty area, drilled a low effort onto the foot of the right-hand post.
Newcastle were fortunate not to fall further behind as Thompson hit the bar for a second time, with the Spurs winger driving into the box before his terrific effort cannoned off the top corner of the right-hand post before the loose ball was cleared to safety.
United suffered a difficult blow in the 76th minute as Scarlett scored Spurs' third, curling a free-kick from the edge of the box into the left-hand corner.
Newcastle conceded a fourth two minutes as Thompson netted Spurs' fourth of the afternoon, collecting Williams-Barnett's pass before firing a low effort into the left-hand corner to round off a tough afternoon for Lawrence's side.
Newcastle United Under-21s: Max Thompson, Leo Shahar, Alex Murphy, Charlie McArthur, Cathal Heffernan (c), Scott Bailey, Alfie Harrison, Rory Finneran (Fraser Harper 61), Kacey Wooster (Joe Brayson 78), Anthony Munda, Dylan Charlton (Mohamed Waddani 71).
Subs not used: Miodrag Pivaš, James Taylor.
