Wednesday saw him suffer a first 6-0 "bagel" at a Slam since the 2005 US Open, while the defeat will see him slip out of the world's top two for the first time in six years. The Austrian then pushed forward, taking the next two sets 6-3, 6-0 and forcing Djokovic to confront a lost set and match for the first time in the tournament.
The Austrian sixth seed swept aside Horacio Zeballos 6-1 6-3 6-1 to book a last-eight clash with Novak Djokovic.
The fourth-seeded Nadal led 6-2, 2-0 when No. 20 seed Carreno Busta stopped after 51 minutes of play.More news: White House: Trump's tweets are 'official statements'
Wawrinka demolished Croatian Marin Cilic 6-3 6-3 6-1 on Wednesday, while Murray tamed Japanese star Kei Nishikori. Just a pretty bad set.
Known for tremendous footwork and court coverage, the No. 2-seeded Serb even stumbled and tumbled to the court, his racket flying out of his hands, early in the second set. "In Rome it was not a good day for me. It's a big challenge, but I'm up for it", added Djokovic.
The second-seeded Djokovic had two set points in the opener but couldn't convert either.
"I am in semi-finals with a very positive feelings", Nadal said.More news: Millwall fan who tackled London terrorists a 'hero' - Carl Frampton
Djokovic was asked during his post-match news conference whether he would prefer to take a break from tennis, rather than play through his issues.
"He's played fantastic this tournament so far", Murray said of the 32-year-old, the oldest Roland Garros semi-finalist since Jimmy Connors in 1985.
"It's tough to get out of it and figure out the way how to move ahead". Nadal is bidding for his 10th French Open title. Murray advanced to his fourth straight semi-final in Paris, defeating Nishikori to avenge his loss to the Japanese star at the US Open a year ago.
Djokovic, whose struggles with form since a third-round exit at last year's Wimbledon have been well documented, had made a steady start at Roland Garros this year with Andre Agassi in his box for the first time.More news: Southwest Airlines 72-hour sale offers round trips for under $100