he injury, sustained in his fourth-round win over Francisco Cerundolo, ended the Serb's quest to win a record-extending 25th Grand Slam trophy and will result in him losing his top ranking to Italian Jannik Sinner on Monday.
Jannik Sinner took an unexpected path to the world number one ranking on Tuesday after Novak Djokovic's French Open withdrawal but the youngster said it was the culmination of years of hard work and represented a proud moment for Italy.
"Due to a torn medial meniscus in his right knee (discovered during an MRI scan performed today), Novak Djokovic... has been forced to withdraw from the Roland Garros tournament," organisers said in a statement.
The Serbian pulled off another astonishing escape as he reached a 15th consecutive French Open quarter-final.
The 24-time Grand Slam title winner made the last 16 by defeating Italy's Lorenzo Musetti in a bruising five-set epic which concluded at 3:07 am Sunday.
His four-hour 29-minute victory also allowed the 37-year-old world number one to equal Roger Federer's record of 369 Grand Slam match wins.
Novak Djokovic can equal Roger Federer's record for Grand Slam match wins by beating Lorenzo Musetti at the French Open on Saturday.
Djokovic, chasing a fourth title at Roland Garros and record 25th Grand Slam triumph, came through against 142nd-ranked French opponent Pierre-Hugues Herbert 6-4, 7-6 (7/3), 6-4.
World number one Novak Djokovic admitted he was "worried" about his French Open title defence after falling to 44th-ranked Czech Tomas Machac in the Geneva semi-finals on Friday.
Tennis superstar Rafael Nadal said Monday returning to action at the Barcelona Open is a "gift" and he wants to enjoy every moment of what he expects to be the last year of his career.
Novak Djokovic admitted he was "not having a great season at all" after he was knocked out of the Monte Carlo Masters by Casper Ruud in the semi-finals.
Casper Ruud finally defeated Novak Djokovic at the sixth attempt on Saturday, setting up a Monte Carlo Masters title showdown with Stefanos Tsitsipas.
An inspired Stefanos Tsitsipas handed Jannik Sinner his second loss of the season on Saturday as the two-time champion reached the Monte Carlo Masters final 6-4, 3-6, 6-4.
Djokovic will take on either Casper Ruud of Norway or France's Ugo Humbert for a place in Sunday's final.
World number one Novak Djokovic said his "feeling was great" as he flew past Roman Safiullin in straight sets at the Monte Carlo Masters on Tuesday, after third seed Carlos Alcaraz withdrew from the event due to injury.
Rafa Nadal's withdrawal from the Monte Carlo Masters has cast doubt over the 22-times Grand Slam champion's participation at the French Open, but Novak Djokovic said he is still hoping for a final chapter in their storied rivalry.
Djokovic has had a poor start to the year by his standards.
Novak Djokovic and Goran Ivanisevic are to go their separate ways, the tennis world number one announced on Wednesday, ending a five-year association which yielded 12 Grand Slams.
World number one Novak Djokovic withdrew from next week's ATP-WTA Miami Open on Saturday in the wake of his shock exit at Indian Wells.