The deadlock in the London derby on the banks of the Thames was broken in the 55th minute when Spurs midfielder Sandro collected the ball just inside the Fulham half, advanced a few steps towards goal and unleashed a low bouncing shot towards goal.
Veteran goalkeeper Mark Schwarzer looked to have it covered but seemed to take an age getting down to cover his right-hand post and allowed the ball to slip through his palms for a very soft opener.
And the contest was effectively settled in the 72nd minute when Defoe applied the finishing touch from 10 yards out after substitute Gylfi Sigurdsson had turned Philippe Senderos inside out on the edge of the Fulham box.
Clint Dempsey then played a neat ball through the Fulham defence with Senderos failing with his attempts to play offside, allowing Defoe to race clear and again beat Schwarzer just five minutes later.
But the victory was tempered by injuries to centre-back Michael Dawson, who limped out in the first half, and winger Gareth Bale, who pulled up with a hamstring problem in the second period and was replaced by Sigurdsson.
Bale endured a miserable afternoon overall, as he was booked for diving in the first half after falling theatrically over Steve Sidwell's outstretched leg and then risking further punishment with his sarcastic applause of referee Chris Foy's decision.
Dempsey had the first chance of the contest with only five minutes on the clock when he was fed by Defoe before wriggling clear of his marker on the edge of the box only to curl his low shot narrowly wide of Schwarzer's goal.
Fulham's first opportunity fell to Kerim Frei in the 12 minute, but he could not control his side-footed effort from the edge of the area after good work from Dimitar Berbatov and Ashkan Dejagah.
Hugo Lloris, who had very little to do for long periods, produced a smart stop to deny Mladen Petric midway through a disappointing first period, getting down quickly at his near post to deny the Cottagers forward after a quick ball in from the left flank.
Spurs then took control after the interval, with Schwarzer's error gifting them the lead from Sandro's somewhat speculative effort before Defoe's quick-fire brace made the game safe.
The victory lifts Andre Villas-Boas' men level on points with his former club Chelsea in the table on 26 points from 15 games, while Fulham are heading in the opposite direction on the back of their miserable recent run of no wins from seven.