Dempsey, who refused to play for Fulham early this season while awaiting a transfer, was mocked by the home support throughout the match but added a late assist on a perfect through ball to Defoe.
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 Defoe, who so often lived in the Bulgarian's shadow at White Hart Lane, who stole the show Saturday by bagging his 11th and 12th goals of the current campaign.
Defoe this week spoke about how working under Andre Villas-Boas had breathed life into his career, and the 30-year-old delivered once again for his manager by killing off the game with Tottenham's final two goals.
Villas-Boas was left in awe of the in-form striker's exploits.
"It was amazing," Villas-Boas said. "Sometimes strikers look distant from the game but when the team sets them up it's important that they have that clinical touch and he just has it. He is having an amazing season with us. He is playing lots of games and is extremely motivated."
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 Dempsey's pass.
The win -- Tottenham's third in a row, now means Villas-Boas' team is level with third-place Chelsea in the table.
Fulham has now failed to score in its past three matches, and manager Martin Jol rued the way his team collapsed in the second half.
"It was a bad result," he said. "It was a tight game but the likes of Gareth Bale, Aaron Lennon, Clint Dempsey, Jermain Defoe ... we kept them pretty quiet. It was very disappointing to concede three goals out of nothing."
Elsewhere, Harry Redknapp's home debut in charge of Queens Park Rangers ended in a 1-1 draw against Aston Villa at Loftus Road, in a game from which both sides will be frustrated not to have claimed all three points.
The home side largely controlled the second period but were almost made to pay for their missed chances when Villa substitute Karim El Ahmadi fired just wide with two minutes to go.
Redknapp was encouraged by what he saw in his first home game in charge and believes his players can count themselves unlucky not to have won.
"We need a win, we need to get win on the board somehow," the QPR boss said. "We had people out there like Clint Hill and Ryan Nelsen today. Ryan came here and probably felt he was going to be fourth-choice center half and he is playing every week and is captain."
Daniel Agger's 43rd minute header proved enough as Liverpool chiseled out a 1-0 win over struggling Southampton at Anfield.
The home side largely dominated with Jonjo Shelvey hitting the post in the 36th minute, then a Luis Suarez free kick rebounded off the bar and fell to Glen Johnson, whose cross back into the box set up the winner for Agger.
"The game should have been put to bed well before it was," said Liverpool manager Brendan Rodgers. "I thought we were outstanding the first half."
Substitute Dean Whitehead snatched a 75th minute winner for Stoke at The Hawthorns as West Brom fell to its second successive defeat.
A dismal game sprang to life in the final quarter hour after Whitehead -- a 54th minute replacement for Charlie Adam -- poked home from a ball into the box by Michael Kightly to give the Potters a 1-0 win.
"I've not turned into a genius," said Stoke boss Tony Pulis about his substitution. "It's just the little bit of luck you need."
Information from Press Association was used in this report.