Nadal's canter past Gael Monfils on Wednesday made it 20 wins in a row on clay for the Spaniard, and he can set a new record for consecutive sets won on a single surface next time out.
Britain's Kyle Edmund enjoyed one of the biggest triumphs of his career by defeating Djokovic 6-3 2-6 6-3.
Meanwhile, former British number one Andy Murray is doing "everything he can" to be fit for Wimbledon, according to his mother Judy. However, second seed Caroline Wozniacki and third-seeded home hope Garbine Muguruza both fell to shock defeats.
We are not watching peak Djokovic, but this was still a major scalp - taken amid the pressure of a deciding set where Edmund has often struggled over the past 18 months. He reached the French Open quarter-finals past year and made the semis in Barcelona earlier this month. The 30-year-old has shown glimpses of his best this week but those moments have still been few and far between. I believe a lot in dynamics, in momentum.
"There are obvious things that are not working well for me".
'These are things that matter, things that happen.
"But I can be happy with the progress of the level of my tennis. I don't have any doubt of that".
Djokovic was broken to love at 2-2 but he recovered well by pouncing on his opponent's second serve to clinch the opening set in just over an hour.
"It was a great experience first of all to beat Novak, I've lost to him three times", said Edmund, who is set to surge into the top 20 of the world rankings for the first time following this win.
"Obviously I'm disappointed from losing this match", Djokovic said after losing his second round clash.
'It's only the quarter-finals, there are so many good players so it's a tough question, ' Goffin added.
Belgium s David Goffin, whom Edmund lost to on clay during Britain s run to Davis Cup glory in 2015, now awaits in the last 16.
"It s not the end of the world", Djokovic said. "Goffin is a top player so I'm very pleased".
"I tried, but obviously, [it] wasn't to be today". I do it because I like it.
"I'm proud of his strength, determination, love for what he does".
A clear favourite to claim his 11th title at Roland Garros, Nadal will now face Diego Schwartzman of Argentina in the last 16.
"I have done a lot of things well since I came back".
"If I don't pull the trigger too often then I play well". My backhand is working great.
Nadal, who received a bye in the opening round, fired 17 winners and went on to lose just one of 13 service points in the second set to seal victory.
Edmund next plays eighth-seeded Belgian David Goffin, who defeated Dutchman Robin Haase 7-5, 6-3.