The world number one also became the first man to win five Roland Garros crowns in succession as the 28-year-old took his record at the tournament to 66 wins against just one defeat.
His tally of 14 majors equals the mark of Pete Sampras and puts him just three behind the all-time record of Roger Federer who is almost five years older.
Defeat was cruel for world number two Djokovic, the 2012 runner-up, who still needs a French Open title to become just the eighth man to complete the career Grand Slam.
Rafael Nadal celebrates after his victory over Novak Djokovic. Pic/AFP
The Serb dominated the early stages of Sunday's final, the pair's 42nd meeting, seemingly immune to the sweltering 30-degree heat on Philippe Chatrier court. But Nadal, playing in his 20th Grand Slam final to Djokovic's 13th, grew stronger as the final wore on as he ended a four-match losing streak against his old rival.
The 3hr 31min duel ended on a sour note when Djokovic double-faulted on match point, shaken by a shout from the crowd. In a tense opening to their seventh Grand Slam final meeting, the steadier Djokovic, sporting a white cap against the fierce sun, pounced to break for 5-3, after Nadal put too much zip on a forehand.
The Spaniard had two points to break back in the ninth game but two more ballooned forehands kept Djokovic, who had even served and volleyed at 0-30, in the picture.
Rafael Nadal holds the Musketeers trophy after winning the 2014 French Open at Roland Garros. Pic/AFP
He took the opening set when Nadal, off balance and stranded behind the baseline, went long with a slapped backhand.
It was only the second time the champion had dropped the opening set of a final in Paris -- in 2005 against Mariano Puerta and in 2006 against Roger Federer.
However, he regained the advantage with a break to lead 4-2 in the second set with an inside-out forehand stretching the Serb who could only net a desperate return.
But back came Djokovic for 3-4 after a sloppy Nadal service game punctuated by an untimely second double fault.
The world number two saved a break point to go to 4-4, Nadal then held before Djokovic suffered his first serious lapse which was as sudden as it was surprising.
A wild forehand gifted Nadal two set points and the top seed converted with a merciless, crunching forehand. Djokovic was rapidly wilting in the Paris heat as a 22-shot rally laid the foundation for a Nadal break for 2-0 in the third set, courtesy of a weary backhand volley into the net.
A love service game followed for 3-0 with Nadal having taken five games in succession.
Djokovic had break points in the fifth game as well as an 11-minute seventh game but had no response to Nadal's iron will and rock-solid defence.
As the sun disappeared, so did Djokovic's hopes as Nadal claimed the third set off a long forehand from the Serb.
Djokovic appeared to vomit early in the fourth set and he was feeling even worse when he was broken in the sixth game as Nadal again turned defence into scintillating attack.
In keeping their gripping eight-year rivalry, however, Djokovic ensured another twist with a break back for 3-4.
But Nadal clinched victory on Djokovic's third double fault with his second serve interrupted by a scream from the crowd.