Djokovic, a two-time Miami winner and the event's defending champion pushed past 17th-seeded Frenchman Richard Gasquet 7-5, 6-3, improving to 17-2 this year.
Meanwhile, Nadal -- who lost to the Serbian star in last year's final -- made the quarterfinal round with a straight-set win over Japan's Kei Nishikori, 6-4, 6-4.
The former world No. 1 racked up four service breaks compared with only two for the Japanese.
Nadal, a 10-time major champion, has been the runner-up at Miami three times and is still seeking his first title at the event, as well as his first overall since last year's French Open.
American Mardy Fish gained the quarters as well. The eighth seed recorded a 6-3, 6-7 (2-7), 6-3 victory over 12th-seeded Nicolas Almagro of Spain.
Swim Week Miami Beach 2014 [PHOTOS]