Neil Warnock's side took the lead in the first half thanks to a goal from Luke Varney after poor defending from Spurs and they doubled their lead shortly after the break.
Ross McCormack got the goal in spectacular fashion in the 51st minute, and although Spurs pulled one back through Clint Dempsey seven minutes later, the hosts held on for a famous win.
Leeds boss Warnock made just the three changes from the side that beat Bristol City last weekend, with Jamie Ashdown replacing Paddy Kenny in goal.
Ross Barkley dropped out of the midfield for Paul Green and Varney took the place of Leeds' most notable absentee, Luciano Becchio, who looks to be nearing the Elland Road exit door.
After their 1-1 draw against Manchester United, Andre Villas-Boas replaced Hugo Lloris, Michael Dawson, Kyle Walker, Moussa Dembele and Jermain Defoe with Jan Vertonghen, Benoit Assou-Ekotto, Tom Huddlestone and Gylfi Sigurdsson.
The hosts started well as they pressed and hassled Spurs in midfield, but it was the visitors who should have opened the scoring in the first few minutes as Sigurdsson headed Vertonghen's cross straight into the arms of Ashdown.
If Spurs did not already regret that miss, they did a few minutes later as Kyle Naughton and Steven Caulker both failed to clear Michael Brown's hit-and-hope pass, allowing Varney to march towards goal and place the ball in the far corner of the net.
The visitors were struggling to create chances throughout the first half but Gareth Bale should have done better when he got in behind Aidan White and shot at Ashdown, failing to take the opportunity to chip the ball over the on-rushing goalkeeper.
Varney soon had another chance as he linked up well with El-Hadji Diouf down the left and cut inside to shoot, but his effort sailed well over as Leeds took a 1-0 lead into the break.
Things started familiarly in the second half as Spurs looked the more likely to score the next goal, but Leeds caught the visitors on the counterattack when Diouf and McCormack linked up well. The Scot latched on to a ball over the defence before cutting inside Caulker and placing a marvellous shot into the top corner.
Leeds' two-goal lead lasted no more than seven minutes as the quiet Bale burst into life down the left, keeping the ball from Green and Sam Byram before crossing for Dempsey to glance the ball into the far side of the goal with an excellent header.
A few minutes later, the hosts should have restored their two-goal lead as Diouf and McCormack combined again and a slip from Vertonghen saw the latter break free, but Friedel palmed his shot around the post.
A fantastic long-ball from Benoit Assou-Ekotto played substitute Jordan Obika through in the dying minutes, but the youngster, under pressure from Lees and Peltier, put his shot well over from a great position and Leeds held on for the win.