It was 24-time Grand Slam champion Djokovic's 31st win in a rivalry which began on the same Roland Garros clay courts in 2006.
Nadal was largely outclassed in the much anticipated encounter, only coming briefly to life when he won four games in a row in the second set.
"I'm very relieved," said Djokovic. "Everything was going my way, I was 6-1, 4-0 up but I played a sloppy service game and gave him chances."
He added: "I never thought back in 2006 that we'd still be playing each other almost 20 years later."
In a sign of the wear and tear the pair have endured in recent months, Djokovic wore a protective strapping around his right knee while Nadal's right thigh was heavily strapped.
But Djokovic played freely, forcing Nadal to scamper around Court Philippe Chatrier where the Spaniard had collected 14 of his 22 Grand Slam titles.
The Serb raced to 4-0 lead, on the back of a double break, and held for 5-0 before Nadal stopped the rot much to the relief of a packed, sweltering crowd.
Djokovic pocketed the one-sided opener when 2008 Olympic gold medallist Nadal ballooned a forehand wide of the mark.
The statistics made grim reading for the 38-year-old who managed to eke out just four points off the Djokovic serve in the first set.
There was no respite for Nadal, playing just his seventh tournament of an injury-plagued season, as Djokovic again carved out a double break for a 4-0 lead in the second set.
Djokovic, seeking a first Olympic gold medal to add to his 24 Grand Slam triumphs, surprisingly handed Nadal a lifeline when he served up a double fault to be broken for the first time.
Nadal retrieved the second break to claw his way back from 0-4 to 4-4 as the top seed went suddenly off the boil.
Djokovic responded in style, a drop-shot leaving Nadal flat-footed as the Serb broke for 5-4 on a fourth break point and clinched victory in style with an ace.
Despite his defeat on Monday, Nadal still has hopes of a gold medal in the men's doubles where he is playing alongside Carlos Alcaraz.
