World number two Djokovic, on a run of 37 successive wins this year, was placed in the same half of the draw for the second grand slam event of the season as Federer, the 2009 champion and 16-time major winner.
Both men are seeded to reach the last four at Roland Garros, but despite the Serb's undefeated run in 2011, which has left him just five wins shy of John McEnroe's 1984 mark of 42, Federer will be feeling undaunted.
Third seed Federer has lost his last three meetings to Djokovic, the Swiss still holds a career 13-9 winning record over the Serb and is 2-1 on clay.
Nadal, however, leads Federer 16-8 in head-to-heads, 11-2 on clay and is 4-0 at Roland Garros.
World number one Nadal, bidding to equal Bjorn Borg's record of six French Open titles, tackles giant American Isner in his opener.
Isner set a grand slam record at Wimbledon last year when he won a 11 hour five minute second round tie against Nicolas Mahut of France.
Djokovic, twice a semi-finalist in Paris, begins his campaign against Dutchman Thiemo de Bakker, the world number 71 while Federer faces Spain's Feliciano Lopez.
World number four Andy Murray, who was within two points of beating Djokovic in the Rome Masters semi-finals last week, faces a qualifier in his first round.
Former US Open champion Juan Martin del Potro, who made the 2009 semi-finals before losing a five-setter to Federer, is a dangerous floater in the draw and the big Argentine tackles Ivo Karlovic in his opener.
Del Potro, who has been struggling with a hip injury, is a potential third round opponent for Djokovic.
Missing from the draw, however, was America's former world number one Andy Roddick and Spain's 2003 champion Juan Carlos Ferrero who both pulled out late Thursday with right shoulder injuries.
In the women's draw, top seed Caroline Wozniacki begins against Japanese 40-year-old Kimiko Date-Krumm who became the second oldest woman to win a match at Roland Garros when she knocked out Dinara Safina last year.
Safina is one of a host of major names missing from the women's draw this year.
Both Serena and Venus Williams are absent, leaving US Open and Australian Open winner Kim Clijsters amongst the favourites.
Clijsters, who has been bothered by an ankle injury, faces Anastasia Yakimova of Belarus in her first round while triple major winner Sharapova takes on Croatian veteran Mirjana Lucic, a Wimbledon semi-finalist in 1999.
Defending champion Francesca Schiavone of Italy begins against Melanie Oudin of the United States.
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