A leg injury knocked her out of the Rogers Cup in Toronto this month.
"Unfortunately I will not be able to compete in this year's US Open," Sharapova said on her Facebook page Sunday. "I have done everything possible to be ready but it was just not enough time. To all my amazing fans, I will be back in the Asian swing in a few weeks and look forward to finishing the year healthy and strong."
Sharapova, the No. 3 ranked women's tennis player in the world, No. 2 seed at the U.S. Open and five-time Grand Slam winner, was scheduled to play Australian Daria Gavrilova on Monday.
Fellow Russian Daria Kasatkina, who is ranked No. 133, will take Sharapova's place in the tournament.