The France playmaker sent Spurs keeper Brad Friedel the wrong way to slot home comfortably after being brought down by Rafael van der Vaart in the 80th minute.
The Toons top-scorer in the previous campaign, Demba Ba gave Newcastle a lead in the 55th minute before Defoe got Spurs back in the game.
Manager Alan Pardew was sent off to the stands after overreacting with the linesmen for a controversial decision. However, Spurs should have taken the lead in the first half after Gareth Bale and Defoe hit the woodwork.
Jake Livermore sent a neat through ball to Defoe who was clear in front of goal but the 29-year old hit the base of Tim Krul's post while Bale headed towards the bar after meeting Aaron Lennon's cross. Spurs new signing Gylfi Sigurdson made a bright debut as the former Swansea players creativity produced several goal-scoring opportunities.
Andre Villas-Boas may have to rethink his tactics next time around after his men squandered many chances while Pardew will be happy to begin the new campaign with a win.