The visitors raced out of the traps at Staplewood, scoring twice inside the opening eight minutes courtesy of Cristian Ceballos and then Jon Obika.
Sam Hoskins pulled a goal back five minutes before the break, but the north Londoners restored their lead five minutes into the second half when Ceballos struck again.
The Spaniard completed his hat-trick just after the hour mark, with Calum Chambers' heavily-deflected effort deep into injury time proving little more than a consolation.
Saints Under-21 Coach Martin Hunter neglected to name any overage players in his 16-man squad, meaning there was a Barclays U21 Premier League debut for goalkeeper Will Britt between the sticks.
Jordan Turnbull was restored to defence, while Corby Moore and Lloyd Isgrove were also added to the team to make up the alterations to the side which started at Manchester United a week ago.
Among Spurs' XI was former Saints loanee Iago Falque, while fellow starters Obika and Tom Carroll have also spent temporary spells in the npower Championship in previous seasons.
It took just six minutes for the visitors to open the scoring as a neatly-worked corner routine saw the ball find its way to Ceballos, who drilled home from the edge of the Saints area.
Spurs' second arrived just two minutes later as a speculative effort from Falque caught Britt cold before coming back off the crossbar and falling advantageously for Obika to tap into the empty net.
Saints' top scorer Hoskins almost immediately halved the deficit when he found space on the right side of the box but his low shot was excellent saved at the near post by Tottenham goalkeeper Lawrence Vigouroux.
The visitors had further opportunities to extend their lead but former Crystal Palace and Millwall loanee Obika could not force the ball home while Grant Hall headed an Alex Pritchard corner over.
Falque then squeezed a shot past Britt but Luke Shaw got back to hack the ball to safety, before Isgrove and Hoskins saw close-range attempts at goal go awry.
HOSKINS did manage to add his sixth of the season five minutes before the break when he sprang the offside trap before holding his nerve to slot past Vigouroux.
That gave Saints optimism going into the break, but any hopes of a comeback took a massive blow just five minutes after the restart when the ball fell nicely for Ceballos to finish well despite Britt getting a hand to the ball.
Skipper Ben Reeves went close with a 58th-minute shot that drew an excellent save out of the visiting goalkeeper, but Spurs effectively ensured their victory four minutes later. Obika's flick played in Falque, who squared for Ceballos to thunder into the unguarded net for 4-1.
Coach Hunter – who had already replaced Isgrove with Omar Rowe at the break – brought on Joe Curtis for Corby Moore as he looked to get his side back into the game.
Hoskins could have added his second when he latched onto a Rowe pass and shot towards goal but Vigouroux saved superbly with his legs before the resultant corner was headed wide by Chambers.
With 13 minutes remaining, Saints gave an under-21 debut to Ryan Seager, who has scored eight times for Jason Dodd's U18s this season.
Reeves then saw a free-kick go behind via the crossbar, before Saints' luck was compounded as Luke Shaw was forced off through injury with all three substitutions already used.
Rowe then sent a shot over before, at the other end, Britt denied Tom Carroll at point-blank range and Victor Zapata-Caicedo headed wide from a corner.
CHAMBERS scored with the final kick of the game in last week's 3-3 draw at Manchester United, and he repeated the feat in this encounter.
A smart move down the right involving Seager and Hoskins led to the ball making its way to the midfielder, whose shot from just inside the area span off Kevin Stewart and inside the far post.
The result means Saints have lost their last two Barclays U21 Premier League fixtures at Staplewood, having been beaten by Stoke City a fortnight ago.
Saints U21: Britt, Young, Stephens, Turnbull, Shaw, Moore (Curtis 63), Chambers, Reeves, Sinclair (Seager 77), Isgrove (Rowe 46), Hoskins. Subs not used: White (GK), McCarthy.
Goals: Hoskins (40), Chambers (90+4)
Spurs U21: Vigouroux, Barthram, Stewart, Gardiner, Hall, Carroll, Falque, Parrett, Obika (Munns 75), Pritchard (Bentaleb 71), Ceballos (Zapata-Caicedo 75). Sub not used: Miles.
Goals: Ceballos (6, 55 & 62), Obika (8)
Gardiner (77), Parrett (90+3)
Highlights of this afternoon's game plus a post-match interview with U21 Coach Martin Hunter will be on Saints Player tomorrow