The 34-year-old from Spain called sitting out the tournament scheduled to begin August 31 in NY "a decision I never wanted to take", but added that he would "rather not travel".
The world no.2 says the complicated coronavirus situation is to blame.
Most of Court's titles came before the Open Era, including Australian Opens that didn't include numerous world's top players.
"We know that the reduced tennis calendar is barbaric this year after 4 months stopped with no play", Nadal wrote on Twitter. We have just seen the announcement of Madrid not being played this year. "This is a decision I never wanted to take but I have chose to follow my heart this time and for the time being I rather not travel".
Swiss Roger Federer, a five-times U.S. Open champion, will also be absent after the 38-year-old was forced to undergo knee surgery in June that prematurely ended his 2020 season.
Swiss Stan Wawrinka was the last player outside the Big Three to win a Grand Slam when he beat Djokovic in the U.S. Open final in 2016 but he too will be absent from NY later this month for as yet undisclosed reasons.
Nadal has since termed the busy upcoming tennis schedule as "barbaric" while confirming he will not stand to retain his US Open trophy.
The Serb, chasing his 18th Grand Slam title, may face off against the likes of other major finalists Dominic Thiem and Daniil Medvedev as well as Greece's Stefanos Tsitsipas and Germany's Alexander Zverev, who also entered the tournament.
That means any potential gain on Nadal for Djokovic in the GOAT race from the U.S. Open could be short-lived.
Organizers confirmed that world number one and three-time victor Novak Djkovic would be among those playing, alongside last year's finalist Medvedev and fellow top 10 stars including Dominic Thiem and Alexander Zverev.
Speaking before his Adria Tour events caused uproar when several participants tested positive for Covid-19 in the wake of social distancing measures not being observed, Djokovic had called the proposed US Open restrictions "extreme".
It was due to be played as the premier warm-up event for the rescheduled French Open which is set to be played at the end of September and plans had been put in place for a bio-secure bubble to be created.