Nadal has won 14 of his 22 Grand Slam titles in Paris but at 38 time is ticking for the Spaniard, who last month suffered his earliest exit from the French Open.
Battered by exhausting, career-long battles with injuries, former world number one Nadal has seen his ranking slump to 161.
As a result he is unseeded at the Games and could come up against top seed Djokovic as early as the second round, in what would be the pair's 60th meeting.
"Roland Garros is the most special place in the world of tennis for me," said Nadal, who won Olympic singles gold at Beijing 2008 and doubles gold with Marc Lopez in Rio eight years later.
Djokovic leads Nadal 30-29 in their head-to-head series.
But Nadal has won eight of their 10 meetings at Roland Garros, triumphing in their most recent clash in the 2022 quarter-finals.
That win helped propel Nadal to a 22nd major title. It was also the most recent of his 92 career singles trophies.
Nadal start his Paris Olympics against Hungary's 83rd-ranked Marton Fucsovics.
Djokovic has traditionally struggled at the Olympics with just a bronze medal from Beijing 2008 to show for his efforts.
He arrives in Paris smarting from a straight-sets loss to Carlos Alcaraz in the Wimbledon final as he was foiled in his bid to win a record-setting 25th Grand Slam title.
Without a title since last year's ATP Finals, Djokovic is enduring a torrid 2024 by his standards.
Jannik Sinner, missing from the Olympics with tonsillitis, succeeded him as Australian Open champion and eventually world number one.
Alcaraz, still only 21, took his French Open title.
Murray farewell
Djokovic, who starts his Olympics against unranked Matthew Ebden of Australia, can at least be confident in his French Open pedigree with three titles in 2016, 2021 and 2023.
With Roger Federer retired, Nadal deep in the twilight of his career and Andy Murray quitting once the Olympics are over, Djokovic finds himself facing down the new generation spearheaded by Alcaraz and Sinner.
Adding to the pressure for the Serb is knowing that should he fail to successfully defend his US Open title in September, it will be the first time in 22 years that none of the "Big Four" have secured a Grand Slam crown.
Alcaraz, who already has four Grand Slam titles, starts his first Olympics against 275th-ranked Hady Habib of Lebanon.
Alcaraz and Nadal are teaming up in doubles for the first time in Paris, where they could find Murray on the other side of the net later in the tournament.
Murray, who won gold at the 2012 and 2016 Olympics, will not play singles in Paris, his last tournament before he retires.
The 37-year-old former world number one and three-time major winner said he "just ran out of time" in his bid to be fit for singles after undergoing surgery to remove a cyst on his back.
Instead he will play doubles with Dan Evans.
Defending Olympic champion Alexander Zverev, seeded third, takes on Jaume Munar of Spain.
Russian fourth seed Daniil Medvedev, playing in Paris as a neutral following Moscow's invasion of Ukraine, will meet Rinky Hijikata of Australia.
Swiatek for gold?
Women's world number one Iga Swiatek, returning to the scene of her fourth French Open title last month, begins against Romania's Irina-Camelia Begu.
The 23-year-old Pole, dumped out in the second round at the Tokyo Olympics three years ago, is the favourite for gold.
US Open champion Coco Gauff, who missed Tokyo with Covid, takes on Australia's Ajla Tomljanovic.
Like Murray, fellow former world number one Angelique Kerber of Germany will retire once the Games end.
The 36-year-old was a silver medallist in singles at Rio 2016.
In a first-round clash of mothers, 36-year-old Kerber faces four-time Grand Slam champion Naomi Osaka of Japan.
The Olympics open on Friday, with the tennis starting the next day.