The Spaniard became the first man to win five successive titles at Roland Garros, coming from a set down to win when Djokovic double-faulted on championship point.
Nadal is now level with legendary American Pete Sampras on 14 grand slam titles overall, with only Roger Federer (17) boasting more.
Second seed Djokovic - seeking a victory that would have completed a career grand slam - got off to a flyer by taking the opening set, but Nadal showed all of his famous spirit to battle back in over three-and-a-half hours of gruelling tennis on Court Philippe Chatrier.
The world number one has now beaten Djokovic on five occasions at Roland Garros, and extended his personal record at the clay-court slam to a scarcely believable 66 wins and one defeat.
Djokovic took the initiative in the eighth game of the first set, breaking Nadal on his third break point to move 5-3 up before then consolidating immediately to move one set up.
Nadal thought he had broken Djokovic for the first time in the match when 3-2 up in the second, but the ball was adjudged to have just landed long.
The 28-year-old put that disappointment behind him, though, breaking in the same game with a strong cross-court forehand that forced Djokovic to send his return into the net.
The Serb, who also lost to Nadal in the 2012 final at Roland Garros, broke straight back, taking advantage of his second break point when the Spaniard made another error on the forehand side.
But Nadal broke again when 6-5 up to level the match, offering his familiar fist-pump celebration after thumping a forehand winner down the line.
The top seed took the early initiative in the third, moving 2-0 to the good when Djokovic sent a routine backhand volley into the net.
Nadal then went ahead in the match with his second break of the set, as an increasingly fatigued Djokovic sent a forehand long.
The Spaniard looked on course for a comfortable fourth set when he broke to move 4-2 up, only for Djokovic to respond with an immediate break back.
However, Nadal was not to be denied, as tiredness apparently got the better of Djokovic when he double-faulted at 30-40 when 5-4 down to ensure the champion's dominance at Roland Garros continues.