Nadal, a 14-time champion at Roland Garros, has been beset by injuries in his final season on tour while Djokovic has failed to reach a final in 2024.
Meanwhile, young Grand Slam champions like Carlos Alcaraz and Jannik Sinner are also nursing injuries, making this year's French Open highly unpredictable.
That has opened the door for the likes of Alexander Zverev, Stefanos Tsitsipas, Casper Ruud and Andrey Rublev to step up and open their Grand Slam account.
Zverev has not had it easy since he injured his ankle in the 2022 French Open semi-final and underwent surgery, but the 27-year-old has peaked at the right time, winning his sixth Masters title at the Italian Open on Sunday.
"Obviously being there (at Roland Garros) three times in the semi-finals in a row, (I was) playing some of the best tennis of my life there when I injured my ankle," Zverev said.
"So in general it is always determined and marked in my calendar throughout the past few years. This year there's no exception.
"That's the one that I want to win. That's the one that I look forward to the most maybe throughout the year. I'm going to do everything I can this year and we'll see where I can end up."
Rublev, meanwhile, overcame the odds and battled through a suspected virus and an anaesthetised foot to win the Madrid Open before returning to the hospital to make a full recovery.
The 26-year-old Russian has fallen at the quarter-final hurdle at every Grand Slam but has two titles under his belt this season to give him a boost.
"For me was just to keep working, to keep trying to improve, because the season is long and we have too many opportunities, so in one moment I will have a chance," Rublev said.
"As soon as I will have a chance, I will need to use it, because this week will change everything."
'Incredible tennis'
Tsitsipas warmed up for Roland Garros by winning his third Monte Carlo Masters title in four years last month, a welcome trophy for the Greek who had won just one ATP 250 title since June 2022.
"If I have to compare my level of tennis with the last two times that I've won here, I'd probably say this time has been the best, that I've come up with some incredible tennis," he said after beating Sinner and Ruud in the semis and final.
"I had an opponent in the semi-final that is a world-class tennis player right now who refused to lose to anyone, and he's been on a very good streak.
"So overcoming that obstacle, it's definitely a sign that my tennis is progressing and I'm able to push those players."
Ruud exacted revenge at the very next tournament in Barcelona when he beat Tsitsipas in straight sets in the final.
The Norwegian will hope it is third-time lucky at Roland Garros after losing the last two finals to Nadal and Djokovic.
Ruud had also played several finals on the ATP Tour without winning before lifting the trophy in Barcelona.
"Honestly, this has been worth the wait," he said. "A lot of finals that I've lost have been tough, a bit disappointing, of course.
"Any time you reach a final, it's nonetheless a good week, so you can't be too hard on yourself, but this one has been a long time coming."