The Spaniard announced his withdrawal from the tournament on Twitter earlier today.
"I am very sad to announce that I am not ready to play the US Open in NY," Nadal, 26, tweeted.
"Thanks to my fans for their support and especially, the New Yorkers."
In a statement, cited by the Los Angeles Times, Nadal said he needed to “continue with my recuperation and preparation to be ready to play in the right conditions."
The former world No. 1, who is currently ranked No. 3, has not played a match since his shocking loss to 100th ranked Lukas Rosol in the second round of Wimbledon on June 28, the New York Times reported.
Nadal, who owns 11 Grand Slams, also missed the London Olympics and the US hard court season due to injury.
It is the first time he will miss the US Open, which he won in 2010.
The Associated Press said Nadal’s relentless style of play has taken a toll on his body, especially his knees, and his withdrawal from the US Open raises doubts about his future in the sport.
The tournament in Flushing Meadows starts August 27.