The pair have won 15 of the last 17 titles at Roland Garros between them, with Nadal claiming 13 of them but losing to eventual champion Djokovic in the semi-finals last year.
They have not met as early as the quarter-finals at any grand slam since the French Open seven years ago but Nadal has dropped to world number five while he goes into the tournament with concerns over a chronic foot problem.
An unbalanced draw saw Carlos Alcaraz, widely considered the most likely challenger to Djokovic and Nadal, also placed in the top half – along with Alexander Zverev – and a potential semi-final opponent for either of the two veterans.
Nadal, who will take on Australian Jordan Thompson in the first round, could meet former champion Stan Wawrinka in round two.
There were good draws for Britain’s two main hopes, with 12th seed Emma Raducanu making her debut at Roland Garros against a qualifier while 10th seed Cameron Norrie will meet French wildcard Manuel Guinard.
Raducanu, who has shown encouraging form in her first professional matches on clay, is seeded to meet Angelique Kerber in the third round and in-form sixth seed Ons Jabeur in the last 16.
Dan Evans, who is seeded 29th but still looking for a first victory at Roland Garros, faces a tougher opener against Argentina’s Francisco Cerundolo.
Rounding out the British contingent, Heather Watson meets French teenager Elsa Jacquemot and Harriet Dart, another debutante, faces former quarter-finalist Martina Trevisan.
Defending champion Barbora Krejcikova, who has not played since February because of an elbow injury, will meet France’s Diane Parry while Naomi Osaka was handed a tough opener against Amanda Anisimova, to whom she lost at the Australian Open in January.
Osaka is back at Roland Garros 12 months after pulling out of the tournament following a row over her appearances at press conferences and opening up about her mental health difficulties.
Action in the main draw begins in Paris on Sunday.