The world number two is widely considered as the biggest threat to Nadal, who became the first man to win the same Grand Slam eight times by defeating fellow Spaniard David Ferrer in last year's final.
Nadal - who has 13 grand slam wins to name - has been crowned champion in eight of the past nine French Open tournaments, with his only defeat at Roland Garros coming in round four back in 2009 when he was beaten by Sweden's Robin Soderling.
Nadal has faced some epic encounters against Djokovic in Paris including the 2012 final, but perhaps last year's semi-final will be best remembered, with Nadal eventually coming through a gruelling five-set contest that lasted over four and a half hours.
The Spaniard's dominance on clay may be under threat, though, as Djokovic has hit form at the right time after problems with injury and form earlier this year.
That was exemplified by the 27-year-old's triumph over Nadal at last week's Rome Masters, a success has convinced Djokovic - winner of six major titles - that he has what it takes to collect the only major missing from his resume.
"Knowing that I have gotten closer and closer each year to the title gives me enough reason to be confident for the start of this year," Djokovic said.
"Winning against Nadal on clay is something that doesn't happen every day so (Rome) definitely helps my confidence, my self‑belief. And I'm healthy and obviously very motivated and inspired to play my best tennis here."
By contrast, Nadal's usually impeccable standards on the red surface has suffered somewhat of a blip, with quarter-final exits in Monte-Carlo and Barcelona, though he did claim victory at the Madrid Open.
However, Nadal - who is gunning to become the first man to win five straight crowns at Roland Garros - is excited to be back in Paris.
"I'm just happy to be back in a place that has given me so much," he said. "This place is the most important place in my career. It's just always very emotional when I have the chance to be back here."
Nadal and Djokovic are the overwhelming favourites for the tournament, but it would be foolhardy to rule out a host of other star names for the second major tournament of the season.
Among the chasing pack are the evergreen Roger Federer, the 32-year-old looking for his second triumph in Paris having defeated Soderling in the 2009 final.
Fellow Swiss Stanislas Wawrinka has had a superb season thus far, as the 29-year-old won the first major of the year by defeating Nadal at the Australian Open and has risen to world number 3.
World number eight Andy Murray has had a somewhat indifferent campaign thus far but the favourites will want to avoid the two-time Grand Slam champion, while the likes of 2013 runner-up Ferrer, Tomas Berdych and home-favourite Jo-Wilfried Tsonga will be looking to make their mark on the marquee tournament.