The Serbian star had won the last three Grand Slam titles, all coming at Nadal's expense in those finals. He was trying to become the first man to hold all four major championships at the same time since Rod Laver won a natural Grand Slam in 1969.
But the French Open has been Nadal's second home. The Mallorcan has lost just once on the famed red clay and Djokovic was appearing in the final of the Parisian slam for the first time.
However, after a blistering start for Nadal on Sunday, the tide appeared to turn in Djokovic's favour as heavier rain began to fall in the third set.
Djokovic won eight straight games after falling behind by two sets and a break. He was up a break in the fourth set and dominating Nadal, who appeared to be flustered by the worsening court conditions as well as his own subpar play. The weather eventually halted play for the day after Nadal finally snapped Djokovic's run with a hold of serve.
Down 2-1 in the fourth set when play resumed Monday, Nadal appeared to regain his confidence.
He broke Djokovic to start Monday's action and soon after a light rain once again began to fall. Play was stopped, but only for a few moments, with Nadal ahead 5-4.
The sun made an appearance and play remained on serve until the final game when Djokovic committed a double-fault on match point.
"It's unfortunate because I think I was playing better and I was feeling really well on the court," Djokovic said about the stoppage on Sunday. "Today he started off really strong. I started a bit slower. It was a little bit unfortunate in that first game, and things turned around."
It was Djokovic's fourth double-fault of the match and three came at critical times. In addition to the final point, he double-faulted once in each of the first two sets to give Nadal breaks of serve.
Nadal also double-faulted four times, but none were at important junctures. He committed just 29 unforced errors, while Djokovic had 53. Most of those mistakes came early, when it appeared as though Nadal would just steamroll another opponent in his favourite venue.
A pair of breaks gave Nadal a quick 3-0 lead Sunday and he was ahead 40-15 in the fourth game. Djokovic quickly regrouped and won the next four points to steal the game and momentum. He followed by winning the next two games to square it, but a double-fault in the following game gave Nadal another break for a 4-3 lead.
After each player held serve, Nadal sealed the opening set in the 10th game. A lengthy rally ended with a brilliant Nadal drop shot to produce a pair of set points at 40-15, but he needed only one as a blistering cross-court winner ended it.
Another Djokovic double-fault gave Nadal the first game of the second set, but the Serb broke back in the fourth game with a perfect lob. Nadal, though, broke again with a forehand winner for a 4-3 lead, and he held serve in the next game before rain stopped play for the first time.
After the delay of just over a half-hour, Nadal came out and broke serve to win the set. Djokovic saved one set point with a service winner, but Nadal ripped a backhand winner to finish it.
Nadal held to start the third set and broke for a 2-0 lead. The super Spaniard had yet to lose a set during the tournament and another straight-set thumping began to appear on the horizon.
Things then changed dramatically, as Djokovic found another gear. He won the next six games to capture the set and did so in rather easy fashion with three breaks of serve.
"First two sets I was serving really bad, and I think I allowed him to put a lot of pressure on my serves and made a lot of breaks," Djokovic noted about his start Sunday. "After that I started serving better and I was in the court, and I was playing really aggressive. Finally, I felt great on the court."
Djokovic's stunning turnaround continued early in the fourth set with a light rain continuing to fall. He broke Nadal to start, then held at love. Nadal began complaining about the wet balls, even going so far as to gently throw one past the chair umpire.
After Nadal finally stopped the Djokovic eight-game streak with a hold of serve, play was again halted because of the weather.
More than an hour passed before officials decided to call play for the day.
Monday's finish marked the first time the French Open didn't end on a Sunday since 1973, when Ilie Nastase beat Nikki Pilic. That men's final ended on Tuesday.
Djokovic had won 27 straight Grand Slam matches entering the final and was bidding for his sixth major title. He fell to 5-3 all-time in Grand Slam finals and dropped to 30-17 in title matches altogether, including a 2-3 mark this year.
"You're living for this moment to play finals of any Grand Slam, and sometimes you win; sometimes you lose," said Djokovic. "I lost this time. But I believe that there are still many years to come, and hopefully I can come back stronger."
It was the fourth matchup between Nadal and Djokovic in a final this year. Djokovic prevailed at the Australian Open in a five-set thriller, but Nadal has won the other three.
In addition to Monday's victory, Nadal also beat Djokovic for the titles in clay-court Masters events in Monte Carlo and Rome. He is 19-14 all-time against Djokovic, including 6-3 in Grand Slam play.
The former No. 1 Nadal improved to an astounding 52-1 lifetime at Roland Garros, with his lone loss coming while playing hurt in the 2009 fourth round against Robin Soderling -- a defeat he avenged in the 2010 final.
Monday's victory also gave Nadal his 50th career title. He is 50-21 all-time in finals, including 4-1 this year. Aside from his four finals against Djokovic, Nadal also captured the clay title in Barcelona.
It's now onto the grass courts for the next month, as Nadal begins preparations for Wimbledon. He is scheduled to play this week at the tuneup in Halle.
Nadal's first-place check is worth more than $1.5 million.