The 20-year-old Rune prevailed in wet conditions as rain continues to affect play in Rome, winning 6-2 4-6 6-2 to earn his second consecutive victory over Djokovic after his win in the final of November’s Paris Masters.
It will be the first time since 2004 that neither Djokovic or Rafael Nadal will be in the final of the Italian Open, according to the ATP.
“It’s really a big win for me,” world No. 7 Rune told the ATP Tour. “Obviously I did it last year in Paris as well, but every match is a huge challenge for me when I play against Novak. He’s one of the greatest that’s ever played the game.
“I knew I had to be at my best … and I was today. I’m super proud of myself and I enjoyed every moment out there. I stay humble of course. I have a lot to achieve. I think you should always be humble. I think I am, I hope so and I hope people see me this way.
“I’m a huge fighter on the court and I leave everything when I play my matches. I’m super proud I was able to get the victory today. I had to fight hard and play my best tennis. Huge credit to Novak, I’m a big fan of his. He’s a huge inspiration and I wish him all the best.”
Defeat marks another disappointing clay court tournament for Djokovic, who has now failed to advance past the quarterfinals in his three events on the red surface ahead of the French Open, which begins on May 28.
The Serb, a six-time champion in Rome, also appeared to be struggling physically during the match and required a medical timeout before going on to win the second set following a rain delay.
Djokovic was making his return to the court following his absence from the recent Madrid Open due to an elbow injury and the 22-time grand slam champion still looked well below his best.
However, credit must go to Rune for a brilliant performance that will cement his place among the title contenders at Roland Garros.
The Dane, appearing in his first Italian Open, will play either Casper Ruud or Francisco Cerundolo in the semifinals as the 20-year-old goes in search of a second career Masters 1000 title.