The pair have faced-off 57 times, with Djokovic holding a marginal 29-28 lead but Nadal outdistances the Serb 10-6 in Grand Slam events, including a sweeping 7-1 record at Roland Garros.
The upcoming match will be their first semi-final meeting since Wimbledon 2018.
Nadal won their last match in the Italian Open final in May this year and has not lost to Djokovic on clay in five years.
World No. 1 Novak Djokovic and No. 3 Rafael Nadal, the two goliaths of the game, are headed for yet another collision in one of the French Open semi-finals tonight.
The winner will meet the survivor in today's first semi-final between No. 5 Stefanos Tsitsipas and No. 6 Sascha Zverev in Sunday's Roland Garros final.
There is no clear favourite whenever these two maestros play against each other. However, one has to give Nadal the upper hand given the match is being played on the Parisian Clay.
Djokovic will be looking for some good old-fashioned revenge against Nadal, who won last year's final for the loss of just seven games. Djokovic was simply pulverized by Nadal in that meeting, and had no answer for the Spaniard's heavy groundstrokes.
Needless to say, he will be hoping for a different outcome this time around. But to do that Djokovic will need to open up the court with angled cross-court shots and use the drop shot to get Nadal off the baseline. The Serb's first serve, which has earned him a lot of free points this tournament, will also need to be on point if he is to upstage the "King of Clay" at his favourite hunting ground.
Djokovic predicted a "great battle" when he continues tennis's most prolific rivalry in today's semi-final.
"It's not like any other match. Let's face it, it's the biggest challenge that you can have playing on clay against Nadal on this court. It doesn't get bigger than that.
"There's that extra tension and expectations. The vibes are different walking on the court with him. But that's why our rivalry has been historic I think for this sport.
"I'm confident. I believe I can win, otherwise I wouldn't be here. Let's have a great battle."
Rather unusually, they are meeting in a semi-final than a final, courtesy of Spaniard Nadal having dropped down to world number three and being placed in the same half of the draw as top-seeded Djokovic.
Should Djokovic manage to get the better of Nadal on Friday he will be the favourite to take only his second French Open title having won it in 2016 when Nadal abandoned the tournament due to a wrist injury.
Since then, Nadal has been unbeatable, extending his record title haul to a jaw-dropping 13.
"Obviously it's a well-anticipated semi-final," said Djokovic, who has 18 Grand Slam titles, two behind the men's record shared by Nadal and Roger Federer.