World No. 7 Holger Rune sent a frustrated Novak Djokovic tumbling out of the Italian Open on Wednesday as the young Dane prevailed 6-2, 4-6, 6-2 in an epic battle against the defending champion to secure his place in the semi-finals. 

For the first time since 2004, neither Djokovic nor the injured Rafael Nadal will be in the Rome final. 

Rune outlasted Djokovic in three sets in last year's Paris Masters final and the 20-year-old made the perfect start in search of another upset by breaking the world No.1 in the opening game of the match.

The seventh seed showcased his aggressive style and mixed up his game with delicate drops to race ahead 4-1 as Djokovic looked uncomfortable in between points having admitted a day earlier that he was dealing with physical issue.

Djokovic took a painkiller midway through the second set and the 35-year-old roared back to life to go up 5-2 following a break and a hold, as Rune completely lost his cool over a line call by the chair umpire.

Rune dominated the decider and pounced on Djokovic's serve en route to a 4-0 lead and completed a famous win. 

The Serb, who will drop to second on Monday in the world rankings behind Carlos Alcaraz, admitted that he was outplayed in heavy, wet conditions after a week of rain in normally sunny Rome. 

"This is probably the coldest, wettest tournament I've ever played here in Rome," the 22-time Grand Slam winner said, "...In these conditions, it's very difficult to get the ball past him."

"It's really a big win for me," Rune said. "Obviously, I did it last year in Paris, but every match is a huge challenge when I play Novak.

"He's one of the greatest to ever play the game so I knew I had to be at my best. I'm super proud of myself and I enjoyed every moment out there."

Denmark's Rune will next face French Open runner-up Casper Ruud who prevailed 7-6(5) 6-4 over Francisco Cerundolo to advance to the last four.

In the women's draw, Jelena Ostapenko reached the semi-finals in Rome for the first time after holding off a mid-match surge from Paula Badosa to claim a 6-2, 4-6, 6-3 victory. 

Ostapenko, the 2017 French Open winner, will face seventh seed Elena Rybakina for a spot in the final after world No.1 Iga Swiatek retired from their semi-final with an injury.

(With input from agencies)