Sandro let fly from fully 35 yards for the key opening goal on 56 minutes, the ball zipping in off the post.
Defoe then did what he does best - finishing clinically from substitute Gylfi Sigurdsson's cross on 72 minutes and then calmly slotting home from Clint Dempsey's defence-splitting pass five minutes later.
Dempsey was outstanding on his return to Craven Cottage as the three points lifted us into a share of third place with Chelsea and West Brom.
Andre Villas-Boas made two changes to the team that started against Liverpool. Steven Caulker was back in central defence alongside skipper Michael Dawson and Kyle Naughton a straight swap for Kyle Walker at right-back.
Dempsey was everywhere and curled just wide in the fifth minute after a lovely turn lost Philippe Senderos and Aaron Hughes.
Kerim Frei fired Fulham's first sight of goal wide after 13 minutes but then a blow as Dawson limped off with a hamstring injury. He was replaced by William Gallas.
Hugo Lloris' only serious action of the half arrived on 24 minutes when John Arne Riise's low cross from the left was turned on target by Mladen Petric at the near post but Lloris was there to block and hang on to the ball on his goal-line.
Dempsey angled a shot just wide from 25 yards two minutes later and then Fulham were forced into a change as Stephen Kelly came on at right-back for Sascha Riether.
There was one more chance apiece before the break as Petric lashed over from 18 yards and Gareth Bale couldn't quite turn Lennon's cross on target, the ball slightly behind him.
Steve Sidwell dragged an early shot wide at the start of the second half as both teams looked for that all-important opening goal.
We landed that first blow in the 56th minute thanks to a piledriver from an unlikely source - Sandro. The midfielder picked the ball up in space centrally, weighed up his options and just let rip from 35 yards, the ball fizzing home off the post.
That was the key moment. Fulham had to push on and we looked dangerous on the break with the next chance arriving on the hour as Defoe played in Bale, who struck straight at Schwarzer.
Unfortunately, that signalled our second hamstring injury, as Bale clutched the back of his left leg. He limped out of the action, replaced by Sigurdsson.
The back four stood firm against a short spell of Fulham pressure before the second goal on 72 minutes.
This was all about Sigurdsson, who picked the ball up left of centre, turned Senderos inside-out and then squared for Defoe to finish from six yards.
The third and clinching goal arrived five minutes later and owed much to Dempsey's fine pass between Senderos and Hughes to release Defoe, who went through one-on-one and placed his shot into the corner for his 130th Spurs goal.
Sigurdsson curled straight at Schwarzer and the final chance of note fell to substitute Hugo Rodallega, who headed Damian Duff's cross down but couldn't beat Lloris at his near post.
Fulham (4-4-2): Schwarzer; Riether (Kelly, 29), Senderos, Hughes, Riise; Dejagah, Sidwell, Diarra, Frei (Duff, 62); Berbatov, Petric (Rodallega, 79). Unused subs: Etheridge, Baird, Karagounis, Richardson.
Spurs (4-2-3-1): Lloris; Naughton, Caulker, Dawson (Gallas, 18), Vertonghen; Dembele (Carroll, 84), Sandro; Lennon, Dempsey, Bale (Sigurdsson, 62); Defoe. Unused subs: Friedel, Walker, Falque, Livermore.
Yellow cards: Spurs - Bale.
Goals: Spurs - Sandro (56), Defoe (72, 77).
Referee: Mr C Foy.
After an even first half finished goalless, the lads stepped up to the plate to deliver a third win in the Premier League in the space of six days.