The London derby had been billed as a chance for Berbatov to shine against his former club after such a wonderful start to his career in west London, but it was the man who so often lived in the Bulgarian's shadow at White Hart Lane who stole the show by bagging his 11th and 12th goals of the current campaign.
The England striker this week spoke about how working under Andre Villas-Boas had breathed life into his flagging career, and the 30-year-old delivered once again for his manager by killing off the game with Tottenham's final two goals.
Berbatov showed flashes of brilliance in a good first half for Martin Jol's men, but Sandro put Spurs ahead after the break with a 35-yard drive - his second goal for the club.
Defoe then stepped up to the plate to seal the match, converting Gylfi Sigurdsson's pass to make it 2-0 before adding a second five minutes later from Clint Dempsey's pass.
The win - Tottenham's third on the bounce, now means Villas-Boas' team are level with third-place Chelsea in the table, and given current form, it seems only a matter of time before the Portuguese moves ahead of the club who sacked him in March.
The only worry for Villas-Boas is that Gareth Bale and Michael Dawson both hobbled off with injuries.
Berbatov looked determined to make an impression from the start and it took little time for him to turn on the class.
The Bulgarian, who enjoyed two prolific seasons at Spurs before leaving for Manchester United, produced a deft touch to skip past Dawson and carve open the Spurs defence, but Hugo Lloris charged off his lane to collect the ball before Steve Sidwell had a chance to shoot.
Up the other end Dempsey showed a moment of brilliance to turn Aaron Hughes and glide past Philippe Senderos but he shot well wide.
Dempsey, mocked by the home support throughout the match, was then clattered by Mahamadou Diarra, who was lucky to escape without a booking.
Berbatov's class then shone through once again as he released Ashkan Dejagah with a sublime back heel but Kerim Frei could only put the winger's deflected cross over the bar.
Villas-Boas was forced into an early change when Dawson suffered an injury while clearing a cross in the 15th minute. William Gallas came on in his place.
Bale was booked for diving eight minutes later, although replays showed Sidwell caught the Welshman's trailing leg.
The winger, who was booked for the same offence on Wednesday, was lucky not to see red after sarcastically applauding Chris Foy's decision.
The game slowed down from its frenetic opening. Dempsey and Malden Petric both had half chances and Mark Schwarzer sprinted off his line to deny Defoe.
Berbatov nutmegged Aaron Lennon with an exquisite piece of skill, but the England winger soon collected the ball and found Bale, but he skied his finish.
Petric muscled Sandro off the ball and found Sidwell as Fulham pushed for an opener just after the break, but he dragged his shot wide.
Berbatov prowled on the edge of the box, probing at the Spurs defence, but he could not find a way through.
The away side then took the lead out of nowhere. Sandro capitalised picked up Mousa Dembele's pass five yards inside the Fulham half and carried the ball forward before unleashing a powerful drive that flew in off a post past Schwarzer.
Spurs looked to kill the game off moments later through Bale, who galloped down the left after picking up Defoe's pass, but Schwarzer saved well.
That proved to be Bale's last contribution to the game as he hobbled off with what looked like a hamstring problem.
Fulham struggled to get back on the ball and Defoe took full advantage of Spurs' dominance.
The striker broke down the middle to meet the pass of Sigurdsson, who had turned Senderos inside out, and he made no mistake from close range.
Five minutes later and it was game over. Dempsey threaded a perfect through ball past Senderos, Defoe galloped through and slotted beyond Schwarzer.
Spurs took their foot off the accelerator and eased to a morale-boosting victory.
Source: PA