The world number one’s 6-4 1-6 6-4 loss to Norway’s Ruud follows a third-round exit at Indian Wells and a semi-final loss at the Australian Open.
The 36-year-old Serb is still searching for his first title of the year.
“Not having a title is, compared to the last 15 years, not a great season at all,” he said.
“There are positives to take away for sure, but I’m used to a really high standard in terms of expectations and results.”
Djokovic, who has an 11-4 record this year, also lost while playing for Serbia in the quarter-finals of the United Cup in January.
He will hope to win a record-extending 25th Grand Slam title at next month’s French Open.
Against Ruud in Monte Carlo he double-faulted on Ruud’s match point to confirm the result and end a nail-biting deciding set.
Ruud cruised to victory in the opening set, ensuring Djokovic dropped his first set of the tournament, but the top seed fought back well.
The third set swung back and forth but having got himself back into the game on serve at 5-4 down, Djokovic double-faulted to hand Ruud victory.