Djokovic owns the slightest of edges over Nadal in the overall series at 29-28, but there is a good chance that total evens out because of Nadal's clay-court dominance.
Nadal owns a 17-7 record over Djokovic on clay, and he has won the last five meetings between the two stars on the surface.
One of those victories occurred in the 2020 French Open final, which Nadal won in straight sets.
Before Nadal and Djokovic take the court, Stefanos Tsitsipas and Alexander Zverev face off for the other spot in the men's singles final.
Tsitsipas carries a 5-2 advantage in his career over Zverev, and he is looking for his first-ever Grand Slam final appearance. Zverev is aiming for his second berth after losing to Dominic Thiem in the 2020 U.S. Open final.
Rafael Nadal over Novak Djokovic
The third-seeded Spaniard ran through the French Open final a year ago by limiting Djokovic to two games in the first two sets.
Djokovic played better in the third set of that match, but he could not earn a set off the 13-time Roland Garros champion.
The top-seeded Serbian is 1-7 versus Nadal at Roland Garros. The only victory occurred in the 2015 quarterfinals.
Djokovic has taken four sets off Nadal in his seven defeats to the Spaniard on the Paris clay, which is not a promising sign for a victory Friday.
The No. 1 seed has also looked more vulnerable in the last two rounds, as he dropped three sets to Lorenzo Musetti and Matteo Berrettini.
Djokovic found another gear in both matches to close out the Italians, but he can't afford to give such an advantage to Nadal.
Nadal holds a 15-1 set record in this year's tournament. The only dropped set came against Diego Schwartzman in the final eight.
When Nadal has been tested, he has responded with a commanding performance. The latest example of that was winning the final set over Schwartzman, 6-0. He won 22 of the final 26 points to reach the semifinals.
Djokovic could take a set off Nadal on Friday, but it seems unlikely he will break the clay-court dominance of the Spaniard.
Stefanos Tsitsipas over Alexander Zverev
Tsitsipas has had an edge over Zverev.
The fifth-seeded Greek has put together five straight wins over a three-year span against Zverev, and he has looked like the stronger player in Paris over the last week-and-a-half.
Tsitsipas earned the biggest win of any of the semifinalists by knocking out No. 2 seed Danill Medvedev in straight sets on Tuesday.
Just like Nadal, Tsitsipas owns a 15-1 set record this year at Roland Garros. The only set he dropped came at the hands of John Isner.
Prior to Paris, Tsitsipas won a pair of clay-court titles in Monaco and Lyon. He had three losses in the buildup to Roland Garros, two of which came against Djokovic and Nadal.
Zverev is on a 14-set winning streak, but all of those victories came against unseeded players. The draw opened up for him after Thiem was knocked out in the first round.
The sixth-seeded German could turn in a strong match on Friday, but he has not been as successful on clay as Tsitsipas.
The edge on the surface and in head-to-head battles should bolster Tsitsipas' confidence and help him get through to the final to take on one of the giants of the men's game.
Follow Joe on Twitter, @JTansey90.
Statistics obtained from ATPTour.com.