Defoe, Spurs' fifth highest all-time scorer with 143 goals, will be joining MLS side Toronto FC in March in a six million pounds ($9.89 million) deal and scored in the 72nd minute to guarantee all three points at White Hart Lane.
Tottenham are unbeaten in five league matches since Tim Sherwood became manager last month after the sacking of Andre-Villas Boas and the win took them up to fifth in the table.
Palace are now bottom of the standings despite having dominated an opening half in which Jason Puncheon blasted an eighth minute penalty high and wide into the crowd.
Spurs were far better after the break, took the lead through Christian Eriksen, who smashed the ball home from close range after 50 minutes, and sealed the points when Defoe replaced Roberto Soldado in the 58th and scored 14 minutes later.
He collected a clever through ball from winger Aaron Lennon, created space for himself and then fired past keeper Julian Speroni for the kind of typical poacher's goal he has been scoring throughout his career.
Although it was Defoe's 10th goal of the season in all competitions, it was the striker's first in the league and was greeted by a huge roar of delight from the home fans, at last able to relax after Palace ran their side close.
IMPACT PLAYER
"I know Jermain will score in any league in the world wherever he goes," Sherwood told reporters.
"He is a goalscorer, he loves scoring goals and if he doesn't he gets the hump, so he will go home happy tonight."
Defoe, 31, is leaving Spurs after nine years at the club in two spells partly because he has been offered a superb financial package by Toronto, who will make him the highest-paid player in the MLS according to local media reports.
He also wants guaranteed playing time to help boost his chances of being selected for England's World Cup squad -- something he was not getting at Spurs where he has mainly been used as an impact player for the last two seasons.
Sherwood said they would miss the diminutive forward but believed Spurs still had enough attacking options and was not certain to buy a replacement during this transfer window.
"We are not looking to bring in anyone else at the moment," he said. I am not saying we won't but at the moment we have attacking options.
"We have Ade (Emmanuel Adebayor), we've got Soldado, we've got Erik Lamela and Nacer Chadli and they have got goals in them.
"They are settling in at the moment, and hopefully they are more settled by the time Jermain leaves and we don't have to go into the market."
($1 = 0.6066 British pounds)
(Reporting by Mike Collett; Editing by Ken Ferris)
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