The seven-time champion twice let a lead slip away in the fourth set Friday, then came from behind in the fifth to beat the No. 1-ranked Djokovic 6-4, 3-6, 6-1, 6-7 (3), 9-7.
Djokovic, the winner of six major titles, seeks to become the eighth man to complete a career Grand Slam, but he'll have to get past seven-time French Open champion Nadal first.
Djokovic will next play 35-year-old Tommy Haas, who became the oldest French Open men's quarterfinalist since 1971 by beating Mikhail Youzhny 6-1, 6-1, 6-3. Haas is also the oldest man to reach the quarters at any major event since Andre Agassi at the 2005 U.S. Open.
There were moments, as recently as last year, when a body that would not stay healthy and on-court results prompted Bethanie Mattek-Sands to wonder whether it was simply time to call it a career after more than a decade as a professional tennis player.
The 2010 runner-up swept the first nine games Tuesday and drubbed 42-year-old Kimiko Date-Krumm 6-0, 6-2.
Novak Djokovic and Andy Murray have played in the last two Grand Slam finals, and it's easy to imagine their rivalry overshadowing an aging Roger Federer and an injury-plagued Rafael Nadal in the years to come.
After seven months away treating a left knee injury, Rafael Nadal left many questions unanswered in his comeback tournament.
Nadal lost both the singles and doubles finals in the space of a few hours Sunday at the VTR Open in Chile. And Horacio Zeballos, who earned the first title of his career by beating Nadal in three sets, repeated what Nadal has been saying. "Not playing has hurt him," Zeballos said.
Rafael Nadal wants to stop talking about the aching left knee that kept him away from the ATP Tour for just over seven months until his doubles victory Tuesday with Juan Monaco at a little-known clay court tournament in Chile.
