The young Blues found themselves two down within the first half hour thanks to an eight-minute Alex Pritchard brace.
They then halved the deficit just before the break as Sam Byrne beat Lloris, but Spurs restored their two-goal lead straight from the kick-off thanks to a smashing effort by Nathan Oduwa.
Tottenham striker Shaquile Couthirst rounded off the scoring as he slotted the ball past Mateusz Hewelt in the Everton goal to secure the hosts’ first win of the season.
It was a fairly even start for the sides, and Hewelt had to be alert early on to stop a low shot and make a fantastic save from a Pritchard free kick that was bound for the top corner.
But his clean sheet didn’t last long as Pritchard had another free kick, this time slightly closer than the first, which deflected off the wall and in for the first goal of the Barclays U21 Premier League season.
The home side doubled their advantage just a few minutes later, again through Pritchard, who played a one-two before finding the top corner from the edge of the area.
David Unsworth’s side endeavoured to get back into the game and came close on 38 minutes through Gethin Jones’ incisive shot, but his left-footed effort cureld just wide of Lloris’ far post.
But just five minutes later Everton were back in the game. A brilliant move by Conor Grant to release Byrne drew Lloris out of his goal, and the striker made no mistake in sweeping the ball past the goalkeeper to get The Toffees on the board.
The resurgence didn’t last long, as Spurs moved straight back up the other end from the kick-off and went 3-1 up through Oduwa.
Everton were better in the second half and carved out a couple of opportunities, but it wasn’t enough to stop them falling three goals behind as Coulthirst capped off a comfortable victory.
The result from first game of the season puts Spurs in first place and Everton dead last for the time being.
Tottenham Hotspur U21: Lloris (GK), Walker-Peters, Ogilvie, Lesniak, Ball, Carter-Vickers (C), Azzaoui, Harrison, Coulthirst, Pritchard, Oduwa Subs: Voss (GK), Maghoma, Amos, Sonupe, McEvoy
Everton U21: Hewelt (GK), Jones, Robinson, Walsh, Pennigton (C), Connolly, Williams, Davies (Donohue, 67'), Byrne, Evans (Charsley, 81'), Grant Subs: Stanek (GK), Ledson, Charsley, Donohue, Yates
Referee: Carl Brook (Sussex)