The world number one from Serbia, looking to win the only grand slam missing from his collection, will take on either British third seed Andy Murray or Spain's David Ferrer, the seventh seed, for a place in Sunday's final.
Nadal's only previous defeat came in 2009 when the Mallorcan was knocked out in the fourth round by Swede Robin Soderling.
"He is still a champion," Djokovic, who celebrated calmly, told a courtside interviewer in French.
"The tactic was to be aggressive and focused on every point, but it is not easy to do when you play against Rafa here," he said.
Nadal, who was only seeded sixth after a slow start to the season, said: "I'm going to come back next year and I am going to try to be competitive, to try to be better prepared than this year."
While the scoreline was crushing, the result was not the seismic shock that it was six years ago when the unthinkable happened and Nadal lost to Soderling.
Nadal had started Wednesday's match with a 70-1 win-loss record on the Paris clay and had also won his last four grand-slam matches against Djokovic, as well as their six encounters at the French Open.

Latest News from Sports News Desk