In the lead-up to the French Open, Nadal also struggled against Ernests Gulbis, another big hitter.
"It's incredible, I was shocked after the match, it's a great feeling: indescribable, " Gulbis told reporters.
Put Nadal on a wet clay court with Djokovic or even Gulbis, Roger Federer, or Tomas Berdych and he could suffer.
Gulbis served it out to win 5-7 6-3 6-4 to earn a crack at the 11-time grand slam champion.
In other matches, Spanish world number one Rafael Nadal dropped a set before beating Ernests Gulbis 7-5 3-6 6-3.
Then came Rafael Nadal, who ended the 13-match winning streak of Ernests Gulbis yes, that's right, also in three sets.
Meanwhile, Federer clinched a revenge win over Latvian Ernests Gulbis, who beat the Swiss maestro in Rome three weeks ago.
Gulbis then fashioned a break-point chance in game 10, only for Murray to respond with a service winner of his own.
He will now get an extra day's rest before facing Ernests Gulbis of Latvia for a place in the quarterfinals Wednesday.
In the semifinals he will play Latvian Ernests Gulbis, who enjoyed a 3-6 6-3 7-6 win over fifth seed Tomas Berdych.
The win continued Gulbis' impressive 2010, which has seen him claim his first ever ATP Tour title at Delray Beach in February.
Meanwhile, Ernests Gulbis followed up his stunning victory over Roger Federer by ending the progress of Italy's final remaining hope of victory.
Latvian teenager Ernests Gulbis showed impressive maturity to move serenely into the fourth round with a convincing straight-sets victory over Nicolas Lapentti.
In Rome, he nearly lost a set at love against Ernests Gulbis.
Murray went into the match with a 3-0 record against Gulbis and, having beaten him at Wimbledon, was rarely troubled this time around.
Hs patient baseline game helped earn him the first set point at 5-4, only for Gulbis to fire a huge ace out wide.
Djokovic continued to struggle in the second set, falling behind 3-1 as Gulbis showed his first Grand Slam quarterfinal berth was no fluke.
Third seed Djokovic saw off boyhood friend Ernests Gulbis of Latvia 7-5 7-6 (3) 7-5 to reach a fifth consecutive Grand Slam semifinal.
Elsewhere, Latvian qualifier Ernests Gulbis won his third career ATP title by defeating France's Edouard Roger-Vasselin 7-6 6-3 at the Delray Beach International Championships.
Murray never looked like following Karlovic and Wawrinka out of the tournament at the first hurdle, despite occasional moments of brilliance from the talented Gulbis.
The other semi-final will see Fernando Verdasco of Spain, the number six seed, take on Marin Cilic after the Croat qualifier overcame Latvia's Ernests Gulbis 6-4 6-4.
Second seed Novak Djokovic and fourth seed Andy Murray both reached the third round on Tuesday while world number one Roger Federer crashed out to Latvian Ernests Gulbis.
Berdych, who reached the final the year he beat Federer here, lost in a first-round upset Monday, 7-6(5), 7-6(4), 7-6(4) to Ernests Gulbis, a hard-hitting but erratic underachiever.
Gulbis ran 66 meters, according to a graphic on TennisTV.com.
Gulbis, renowned for his fiery temperament, smashed his racket during the first set of his match against Andreas Seppi as he lost five straight games to concede it 7-5.
And on a good day for the home nation, Jamie Murray and American Eric Butorac won their first-round doubles match against Ivan Ljubicic and Ernests Gulbis 6-1 7-6 (7-1).
In the third set he won eight of the final nine points to close out the victory and then gave Gulbis a pat on the chest as both smiled.
The man Federer beat in last year's final, Juan Martin Del Potro, from Argentina, is on course to meet his nemesis again after disposing of Latvian Ernests Gulbis 7-6 6-3.
Australian Open champion Djokovic and Gulbis first trained together as youngsters at the Munich academy owned by former Germany and Croatia Davis Cup coach Niki Pilic and have remained firm friends.
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