Top seed Djokovic, looking for a Roland Garros title to complete a career Grand Slam, claimed his 50th win at the tournament by seeing off Belgian qualifier Steve Darcis 7-5, 6-3, 6-4.
It was the Serb's third win in three career meetings with Darcis, a player nicknamed 'Shark' who dumped Nadal out of Wimbledon in 2013.
But it was a far from a smooth display from the 11-time major winner and three-time French Open runner-up who committed 42 unforced errors.
"He has a lot of talent and it was tough. I am happy to have won in three sets."
Djokovic next takes on Britain's Slovenian-born Aljaz Bedene who reached the third round of a major for the first time with a 7-6 (7/4), 6-3, 4-6, 5-7, 6-2 win over Spain's Pablo Carreno Busta.
Nine-time champion Nadal became just the eighth man to rack up 200 Grand Slam match wins as he saw off Argentina's world number 99 -- and fellow left-hander -- Facundo Bagnis 6-3, 6-0, 6-3.
"The most important thing is a victory in the second round more than the 200 victories," said Nadal, who now has a 72-2 win-loss record at Roland Garros and only dropped three games in his opening victory over Sam Groth of Australia.
Roger Federer, missing from the French Open this year, tops the all-time list of Grand Slam matches won on 302.
Djokovic is sixth on the list with 216 after his win on Thursday.
