She made the announcement on her Twitter account, insisting the decision was made with her health coming before tennis.
Halep has chosen to remain in Europe where she will train rather than take part in the competition at Flushing Meadows, which is due to get underway on 31 August.
The decision comes a day after she outclassed Elise Mertens in the final of the Prague Open to clinch her 21st WTA title.
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The 28-year-old, whose foremost performance at the US Open was a semi-final appearance in 2015, follows closely behind Belinda Bencic to become the latest high-profile player to pull out of the tournament.
“After weighing up all the factors involved and with the exceptional circumstances in which we are living, I have decided that I will not travel to New York to play the US Open,” Halep says.
“I always said I would put my health at the heart of my decision.
“And I therefore prefer to stay and train in Europe. I know the United States Tennis Association and Women’s Tennis Association have worked tirelessly to put on a safe event and I wish everyone there a successful tournament.”
The reigning Wimbledon champion, Simona Halep, joins Ashleigh Barty, defending champion Bianca Andreescu and Elina Svitolina who have already withdrawn.
American great tennis player, Serena Williams, has refused to stay out of the US Open but has instead opted to play in New York, along with Japanese 2018 champion Naomi Osaka, Australian Open champion Sofia Kenin of the United States and Czech world number three Karolina Pliskova.
Serbia’s world number one Novak Djokovic, three-time Grand Slam champion Andy Murray and Daniil Medvedev have decided to compete on the men’s side.