However, a returning Roger Federer and rejuvenated Rafael Nadal will once again stand in his way, AFP reported.
World number one Djokovic completed his first private stranglehold of all four Slams with victory at Roland Garros in 2016.
Having clinched the 2018 Wimbledon and US Open titles and then a seventh Australian Open crown in January this year, the Serb is tantalizingly close to another 'Djoko Slam'.
Federer and Nadal, with 20 and 17 career Grand Slam titles each respectively, may be ahead of 15-time major winner Djokovic in total hauls.
However, they have never managed to hold all four of the sport's greatest prizes at the same time.
It is such a rare feat that only Don Budge (1938) and Rod Laver (1962 and 1969) – all calendar Grand Slams – have pulled off the sweep in the sport's history.
Djokovic, who turned 32 on Wednesday, is playing down his potential date with destiny.
After losing to Nadal in the Italian Open final last weekend, the Serb was in no doubt that it was the Spaniard who would likely be celebrating a 12th Roland Garros title in a little over two weeks' time.
"Nadal, number one favorite, without a doubt – then everyone else," he said.
However, he admitted his Paris triumph of 2016 which gave him his first sweep, is fueling his bid for more history.
"There is an extra motivation and incentive to win Roland Garros because of the opportunity to hold all four Slams, something I did three years ago, and that gives me obviously enough reason to believe I can do it again."
Twelve months ago, such confidence would have appeared reckless when he was shocked by Italian journeyman Marco Cecchinato in the quarterfinals, a defeat which sent him crashing out of the top 20 for the first time in over a decade.
This time around he starts his campaign against Poland's Hubert Hurkacz, the world No. 43 with a potential quarterfinal against Germany's Alexander Zverev who has still to get past the last eight at a Slam.
Federer is returning to Roland Garros for the first time since 2015 having turned his back on clay court tennis to focus on Wimbledon.
This year marks the 10th anniversary of his one and only Paris triumph and should the 37-year-old defy the odds and clinch the 2019 title he would become the oldest Grand Slam champion of all time.
However, Federer admitted his hopes of seeing off Nadal and Djokovic are slim.
"I feel like I'm playing good tennis, but is it enough against the absolute top guys when it really comes to the crunch? I'm not sure if it's in my racquet," he said Friday.
The Swiss star faces Italy's Lorenzo Sonego, ranked at 73 in the first round on Sunday and could meet Nadal in the semifinals.
Nadal, whose record at Roland Garros stands at a staggering 11 titles and a win-loss record of 86-2, claimed a ninth Italian Open title and a record 34th Masters last week.
"I don't care if I'm the favorite," said Nadal who starts against German qualifier Yannick Hanfmann, the world 184 who has never won a Grand Slam match.
"I care about feeling well and playing well."
Nadal's three-set win over Djokovic in Rome was timely as it was his first title of 2019 and had followed three successive semifinal losses at Monte Carlo, Barcelona and Madrid.
The last two of those were against Dominic Thiem and Stefanos Tsitsipas, both of whom play with a one-handed backhand, just like Federer.
Thiem, the 2018 runner-up to Nadal at Roland Garros, has defeated the Spaniard four times on clay.
"There is a new wave coming through with the one-handed backhand that can counter some of Rafa's spins and lefty play," said Federer.
Serena Williams heads into this year's French Open as an outsider for a Grand Slam title for possibly the first time in 20 years, with questions surrounding her fitness after a poor start to the season, while Naomi Osaka looks to solidify her position at the top of the women's game with a third straight major crown.
The 37-year-old Williams is still waiting for a record-equaling 24th Grand Slam triumph, with her last victory coming at the 2017 Australian Open shortly before taking a break from the sport due to pregnancy.
She impressed initially after returning, but last year twice fell just short of drawing level with Margaret Court's mark, losing in the Wimbledon final to Angelique Kerber before her infamous meltdown en route to another final defeat by Osaka at Flushing Meadows.
Williams' 2019 campaign has not gone to plan so far, with a series of injuries seeing her manage just four matches since her Australian Open quarterfinal exit to Karolina Pliskova.
But she is confident her work off the court can help her find her best game in the biggest tournaments.
"I actually haven't been able to train or practice a lot. I was out much longer than I expected," admitted the three-time French Open champion last week in Rome, before pulling out of the tournament ahead of a second-round tie with sister Venus.
"But I did everything I could to stay fit. I knew that I love the clay season and I wanted to be a part of it.
"It's not about today or tomorrow. For me obviously it's about playing well at all the big moments... Obviously the Slams, etc., just getting ready for those events."
Williams will face Russian world number 82 Vitalia Diatchenko in the first round, with the draw also throwing up a mouthwatering potential quarterfinal against Osaka.
Full of confidence
World number one Osaka has not been overly struggling since surprisingly splitting with coach Sascha Bajin in the wake of her Australian Open title.
But the Japanese star has not won a title since, and like Williams, withdrew from the Italian Open through injury before her quarterfinal against Kiki Bertens.
It has still been the 21-year-old's best-ever clay-court campaign, having also reached the last eight in Madrid and the semifinals in Stuttgart, and she feels her big-hitting game is now ready to dominate on all surfaces.
"Roland Garros, that's what I'm dreaming about right now," Osaka, who has never reached the second week in Paris, said.
"If you're talking about longer goals, of course I haven't won Wimbledon yet and it would be really cool to win everything in one year."
She also does not feel that her lack of a title since Melbourne will have a large bearing on her Roland Garros prospects ahead of her opening match against Slovakia's Anna Karolina Schmiedlova.
"I can't necessarily say it's been ups and downs because if I think about it, it's definitely been going up," she said.