Defoe's first-half strike was enough to seal all three points for the home side and make amends for their embarrassing Carling Cup defeat against Grimsby last week.
But the defeat puts more pressure on Fulham boss Chris Coleman who has only managed one victory in the Premiership this season as the Cottagers languish at the wrong end of the table.
Tottenham started the brightest and could have opened the scoring after just two minutes when defender Lee Young-Pyo fired a right-foot shot from the edge of the box that Tony Warner saved well.
The home side were rewarded for their early pressure when Defoe broke the deadlock in the eighth minute.
Skipper Ledley King played a high ball over the top of the Fulham defence. Defoe broke the offside trap and coolly slotted the ball past Warner into the corner of the net for his third goal of the season.
Claus Jensen almost grabbed an equaliser for Fulham on 22 minutes. The Danish international played a neat interchange with Steed Malbranque before seeing his 25-yard shot come back off the bar.
Warner kept his side in the game on 28 minutes when Mido linked up well with Defoe inside the box. The Egyptian striker fired a close-range shot which was superbly tipped over the bar by the Fulham keeper.
Edgar Davids then almost scored his first goal in English football on 38 minutes following his summer move from Internazionale.
Winger Aaron Lennon produced a superb turn inside the box and played the ball back to the experienced midfielder whose fierce drive produced another fine save from Warner in the Fulham goal.
Tottenham were searching for a second goal and almost extended their lead on 49 minutes when Mido picked out Davids, but his fierce shot flew just wide of the post.
Fulham could never be written out of the game at this stage and went close to notching an equaliser on 51 minutes. Luis Boa Morte's ball found Malbranque on the edge of the box and his dipping drive fell inches past the post.
Paul Robinson showed why he is England's number one on 54 minutes when he produced a superb one-handed save to deny Tomasz Radzinski.
Tottenham may be missing Wayne Routledge through injury, but his replacement Lennon more than showed he can compete at the highest level and almost got his name on the score-sheet on 56 minutes.
The former Leeds winger cut inside Fulham defender Moritz Volz and raced towards goal before striking a low drive which was well tipped around the post by Warner.
But Tottenham held on for all three points as they secured their first win since beating Middlesbrough 2-0 over a month ago.