Dominic Thiem demolished defending champion Novak Djokovic in a stunning French Open upset on Wednesday, setting up a semi-final duel against nine-time champion Rafael Nadal.

Austrian sixth seed Thiem sent the world number two crashing to his earliest loss in Paris in seven years with a memorable 7-6 (7/5), 6-3, 6-0 triumph.

It also piled the pressure back onto the 12-time Grand Slam winner to prove that he is still a contender at the majors following a second-round exit at the Australian Open in January.

The defeat was Djokovic's first straight-sets loss at a major in four years and comes just 12 months after he completed the career Grand Slam in Paris.

He then also held all four majors.

Wednesday saw him suffer a first 6-0 'bagel' at a Slam since the 2005 US Open while the defeat will also see him slip out of the world's top two for the first time in six years.

"It's a dream to beat Novak for the first time and reach the semi-finals at Roland Garros again," said Thiem, who was beaten by Djokovic in straight sets in the semi-finals in Paris in 2016.

It was Thiem's first win over the Serb in six meetings.

"It was tricky today, it was windy and cold. It was important to move well and hit clean."

Thiem trails Nadal 4-2 in career meetings but remains the only man to beat the Spaniard on clay this year after winning in the Rome quarter-finals.

"It's always difficult the deeper you go in the draw -- it won't be any easier on Friday."

Djokovic, who teamed up with Andre Agassi ahead of the tournament, squandered two set points in the 10th game of the opener on Wednesday and things got steadily worse.

Thiem pounced on his lifeline, taking the set after 73 minutes when the Serb dumped a backhand in the net.

By that stage, Nadal was already back in the locker room, safely into the semi-finals after his opponent Pablo Carreno Busta had retired with injury over on Philippe Chatrier.

Djokovic, who had needed five sets to beat Diego Schwartzman in the third round, was 3-0 down in the second set with Thiem's unerring accuracy finding the angles.

The world number two had demolished Thiem for the loss of just one game in Rome in April.

But the 23-year-old Austrian was by far the more composed in the tricky cool conditions on Court Suzanne Lenglen.

He wrapped up the set in the ninth game with Djokovic managing just five winners.

The Serb was on the ropes and was broken in the first game of the third set as Thiem edged closer to avenging his semi-final loss last year.

The set was over in 20 minutes with Djokovic having won just eight points, leaving the court with plenty to ponder ahead of Wimbledon next month.