Djokovic was beaten in two hours and 54 minutesWorld number one Novak Djokovic was knocked out of the Monte Carlo Masters after falling to a three-set defeat by Italian 16th seed Lorenzo Musetti.
Djokovic lost his round of 16 tie 4-6 7-5 6-4 in a rain-affected encounter.
Musetti will face fellow Italian Jannik Sinner who came back from a set and match point down to beat Hubert Hurkacz to reach the quarter-finals.
Seventh seed Sinner, a Monaco quarter-finalist last year, beat the Pole 3-6 7-6 (8-6) 6-1.
Defending champion Stefanos Tsitsipas beat unseeded Chilean Nicolas Jarry 6-3 6-4 in his last-16 match.
However, fourth seed Casper Ruud was stunned by German qualifier Jan-Lennard Struff earlier on Thursday.
Norway's Ruud was beaten 6-1 7-6 (8-6) by world number 100 Struff, a result which ended his nine-match winning run on clay that stretched back to July 2022.
Eight-time Olympic champion sprinter Usain Bolt was present on the fifth day in Monte Carlo to watch Sinner secure his spot in the quarter-finals.
After struggling in the first set, Sinner was forced into a tie-break in the second, where he saved match point before rallying to force a deciding set.
The Italian then got himself ahead and secured the win as Hurkacz faded, with the match ended on a double fault by the Pole.
Danish sixth seed Holger Rune is also through to the last eight as Italian Matteo Berrettini withdrew from the tournament with an abdominal injury.
Miami Open champion Daniil Medvedev is also in action later.
