Nadal, who will turn 36 on Friday, puts his record of 109 wins and just three losses in Paris, since his title-winning debut in 2005, on the line against the defending champion.
The Spaniard was taken to five sets for only the third time in his tournament history by 21-year-old Felix Auger-Aliassime in the fourth round.
In the immediate aftermath of that victory, Nadal admitted that not only was this year’s French Open at stake for him but possibly his entire playing future.
“I know my situation, and I accept it. I can’t complain much,” said Nadal, who arrived in Paris unsure if he would be able to take part after suffering a recurrence in Rome of a chronic foot injury which has plagued him for large parts of his career.
“I am just enjoying the fact that I am here for one more year. And being honest, every match that I play here, I don’t know if it’s going to be my last at Roland Garros.
“I went through a tough process again with my foot, so I don’t know what can happen in the near future.”
Overall, Djokovic leads Nadal 30-28 since their first career meeting at the 2006 French Open.
Nadal has a 19-8 edge on clay and has won seven of the pair’s nine meetings in Paris.
Djokovic, however, came out on top in the semi-finals at Roland Garros in 2021 on his way to a second title.
That defeat took a physical toll on Nadal who then skipped Wimbledon, the Olympics and the US Open.
With Djokovic deported from Melbourne on the eve of the Australian Open, Nadal seized the opportunity to claim a record-setting 21st Grand Slam title, breaking a tie with Djokovic and Roger Federer.
Both men are playing in the quarter-finals at Roland Garros for the 16th time.
Djokovic has reached the last-eight with ease. He has won 22 sets in a row, a run stretching back to his Italian Open triumph in Rome.
Adding an extra twist to the clash is a battle of wills over scheduling.
Nadal insists he does not want to play in the night match.
His compatriot, 19-year-old Carlos Alcaraz, who faces Alexander Zverev also on Tuesday, said it would be “unfair” if he was ordered to play after 9pm for the third time.
Nadal and Djokovic have played one match each after dark.
“I don’t like to play on clay during the night, because the humidity is higher, the ball is slower, and there can be very heavy conditions especially when it’s cold,” said Nadal.
Djokovic hinted he would prefer to face Nadal as late as possible.
“All I will say is Rafa and I would make different requests,” he said.
“I’m glad that I didn’t spend too much time on the court up to the quarter-finals, knowing that playing him in Roland Garros is always a physical battle. It’s a huge challenge and probably the biggest one that you can have here.”
Alcaraz is the youngest man to make the last-eight in Paris since Djokovic in 2006.
He boasts a 2022 claycourt record of 20 wins against just one loss. For the year, he is 32-3.
The sixth seed had to save a match point to defeat compatriot Albert Ramos-Vinolas in the second round but has otherwise been unburdened by the expectations on him.
Alcaraz tackles third seeded Zverev having defeated the German in the final of the Madrid Masters where he also knocked out both Nadal and Djokovic.
Zverev, bidding to reach the semi-finals for a second successive year, is also dismissive of night-time conditions.
“I don’t mind the evening sessions when it’s 30 degrees during the day,” said the 25-year-old.
“When it’s 14 degrees, then in the night it’s going to be what, 8, 9, something like that, it gets difficult.
“My serve is going to be even slower, my forehand is going to be even slower. It’s not going to be an easy thing for me to play at 9:30 at night with no sunlight, with no heat, and 8 degrees.”