0832 GMT May 21, 2018
Djokovic had been on course to meet Rafael Nadal in the quarterfinals in Spain but a disjointed display gave Klizan, ranked 140th in the world, a 6-2, 1-6, 6-3 victory, AFP reported.
While Klizan goes through to meet Spanish clay-court specialist Feliciano Lopez in the last 16, Djokovic will now have to reset, with the French Open next month fast approaching.
His latest setback is not the shock it once might have been.
After losing in the Australian Open fourth round in January, Djokovic underwent surgery to correct an injury to his right elbow, which had been troubling him for almost two years.
The problem has coincided with a prolonged slump in form for the 12-time major champion, who has reached only one Grand Slam final since winning the French Open in 2016.
But a reunion with long-time coach Marian Vajda earlier this month had sparked hopes Djokovic could yet steer his career back on track.
There were encouraging signs in Monte Carlo last week, despite a three-set defeat to Dominic Thiem, with Djokovic declaring there he was finally playing without pain.
He was well below his best against Klizan, however, as the Slovak claimed his first victory against a top-20 opponent in just over two years.
After a miserable opening set, Djokovic looked to have found his groove in the second as he dominated from the baseline and began to find the corners with his forehand.
But, while at his best Djokovic was always ice cool under pressure, he buckled in the decider, planting a Klizan lob into the net before a nervy forehand volley conceded the crucial break at 4-3.
Serving for the match, Klizan double-faulted but he had three chances to close out and clinched the second when another Djokovic forehand missed its mark.