Nadal explained his decision on social media Tuesday, saying it was "a decision I never wanted to take." The 34-year-old from Spain noted he would "rather not travel" during the pandemic.
"After many thoughts I have decided not to play this year's U.S. Open," Nadal wrote on Twitter. "The situation is very complicated worldwide, the COVID-19 cases are increasing, it looks like we still don't have control of it.
"We know that the reduced tennis calendar is barbaric this year after 4 months stopped with no play, I understand and thank for the efforts they are putting in to make it happen. ... All my respects to the USTA, the U.S. Open organizers and the ATP for trying to put the event together for the players and the fans around the world through TV."
Nadal beat Daniil Medvedev in five sets to win last year's men's final at Flushing Meadows. That victory gave Nadal four titles at the U.S. Open and a total of 19 across all Grand Slam tournaments, one away from Federer's career mark.
Ash Barty -- the current top-ranked women's player -- previously announced she would miss the U.S. Open, which is set to begin Aug. 31 in New York. Players can withdraw from the tournament until the start of play.
The professional tennis tours have been halted since March because of the coronavirus, with play resuming for women Monday in Palermo, Italy. The first men's event on the main tour is set for later this month.