Nadal, who hasn't won the Italian Open since 2013, will next face Fabio Fognini, who beat Peter Gojowczyk 6-4, 6-4 to reach his first quarterfinal in 11 appearances at his home tournament.
Djokovic came to the tournament with a 3-3 match record this year, losing his last three since the Australian Open.
Dominating with his serve and aggressive baseline strokes, the 6-foot-10 Isner ended a 15-match winning streak for del Potro, who won Indian Wells two weeks ago by beating Roger Federer in the final.
Del Potro will play 20th-seeded Milos Raonic for a semifinal berth whereas Isner will face Hyeon Chung.
Halep played in her third career Grand Slam final at the Australian Open in January, but has yet to secure a Grand Slam trophy.
In his second and final ATP Miami Masters qualifying match, the 25-year-old eased past Ymer 7-5, 6-2 in a one-sided clash that lasted almost one and a half hour.
In his opening round in the main draw, Yuki will fight it out with fellow qualifier Nicolas Mahut, ranked 101, and if he manages to cross the first hurdle he will be up against world number 12 Lucas Pouille.
Paris: Bob and Mike Bryan won their 32nd ATP Masters 1,000 title and 102nd overall here Sunday at the at c, as they beat Marcin Matkowski and Jurgen Melzer.The Bryan brothers won 7-6 (5), 5-7,
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