Nadal's woes meant he entered Roland Garros ranked seventh, which set him on the path to a horror 29th birthday date with Djokovic.
The traffic-stopping 44th showdown between the two was dubbed "The Superbowl on clay" by John McEnroe but there was nothing 'super' about it during the opening exchanges because within a blink of an eye, Djokovic was 4-0 up.
As Djokovic unleashed an assortment of lethal backhands, forehands and volleys, McEnroe exclaimed: "Nadal unbelievably has no idea what he's doing -- that spells trouble."
There was trouble with Nadal's forehand, there was trouble with his usually reliable top spin and there was trouble with his serve.
"Novak had me under control most of the time. He was better than me. That's it, simple," said the sixth seed after suffering only his second loss in 72 matches in Roland Garros.
"I'm gonna fight. I lost in 2009 (to Robin Soderling) and that was not the end. I lost in 2015 and this is not the end," added Nadal, who produced only three forehand winners during the two hour 27 minute mauling.
Even when Nadal came back to level the set at 4-4, his shots seemed to lack the firepower that in the past left countless opponents gasping for air.
Djokovic, who had lost six previous French Open tussles against Nadal, stayed cool and collected throughout the contest to notch up his 21st win against his Roland Garros nemesis.
"It's definitely a big win, a match that I will remember for a long time," said Djokovic.