"I am very sad to announce that I am not ready to play the US Open in NY. Thanks to my fans for their support and specially, the new yorkers," Nadal wrote on his Twitter account.
He hasn't played a match since June 28, when he was upset in the second round at the All England Club by 100th-ranked Lukas Rosol. Shortly after that defeat, Nadal canceled a scheduled charity match against Djokovic in Spain, citing a left knee injury. Nadal has had recurring knee problems in the past.
The 26-year-old Nadal also pulled out of the London Olympics — he won the gold medal at Beijing in 2008, and was supposed to carry Spain's flag in the opening ceremony this time. He also opted not to play in a hard-court tuneup tournament in Cincinnati.
"Rafa has informed us that he will not be ready to compete at the U.S. Open this year and has withdrawn from the tournament," tournament director David Brewer said in a statement issued Wednesday. "We hope to see him back on the court soon and look forward to his return to New York next year."
Play in the two-week tournament begins at Flushing Meadows on Aug. 27.
Nadal's absence immediately leaves a trio of heavy favorites at the last Grand Slam event of the year: defending champion Djokovic; five-time U.S. Open winner and currently top-ranked Roger Federer; and 2008 U.S. Open runner-up Andy Murray, who won the gold medal in singles at the London Games by beating Federer in the final.
Nadal's withdrawal also raises questions about his future. He owns 11 Grand Slam titles, including seven on the red clay of the French Open, but his hard-charging, hard-hitting style of play takes a toll on his body, particularly his knees.
In 2009, he missed Wimbledon because of aching knees, becoming only the second men's champion in 35 years to decline to defend his title at the All England Club.
Federer, in contrast, has played in every Grand Slam tournament since the start of 2000, a streak of 51 in a row.