The Spaniard, a 20-time Grand Slam winner and Olympic gold medallist in both singles and doubles, has shut down his 2021 season due to a lingering left foot injury that has bothered him at different points throughout his career.
The same injury forced Nadal, 35, to miss both Wimbledon and the Olympic Games Tokyo 2020.
"I have been suffering too much with my foot for the last year," Nadal said in a video message to fans. "The foot is not [in] a proper way today. ... I have not practised the way that I need to be competitive, the standards that I want."
"I'm confident that I will recover myself 100 percent and I will be able to fight again for the most important things." - Rafael Nadal
In a truncated 2021 for Nadal, he made the quarter-finals at the Australian Open as well as the semi-finals at the French Open, where he lost to eventual winner Novak Djokovic.
Earlier in the week, defending champ Thiem announced he was ending his season due to a wrist injury, while Federer said last week that another knee surgery would put him out for "many months."
World No.1 Novak Djokovic will no doubt be the favourite in the men's field, which will also feature No.2 Daniil Medvedev and Tokyo 2020 Olympic champion Alexander Zverev.
Djokovic has the chance to gain ahold of the all-time Slam record in men's tennis at the U.S. Open, with himself, Federer and Nadal ties at 20 majors apiece.
The U.S. Open is set to begin 30 Aug. in New York City.