The four-times grand slam winner, who triumphed at Flushing Meadows in 2006, fired coach Jimmy Connors last week after just one match together.
The 26-year-old world number three, who is suffering from inflammation in her right shoulder, said withdrawing from the year's final grand slam was "a really tough decision to make".
"I have done everything I could since Wimbledon to get myself ready but it just wasn't enough time," she said in statement on her Facebook page.
"I have done many tests, received several opinions and it all comes down to taking the proper amount of time to heal my shoulder injury properly.
"It's certainly not an easy decision to make ahead of one of my favourite tournaments, but I know it's the right one that will get me back on the courts soon.
"I plan on taking the next few weeks off, receiving proper treatment and rehabilitation."
Sharapova lost to 20-year-old American Sloane Stephens in the second round of the Western and Southern Open in Cincinnati last week in her only match since a second-round exit at Wimbledon.
Her absence from Flushing Meadows at least puts to rest widely reported plans she had to legally change her name for the U.S. Open in a publicity stunt for her candy business.
Defending champion Serena Williams is the top seed for the U.S. Open at Flushing Meadows in New York, ahead of Belarusian Victoria Azarenka and Poland's Agnieszka Radwanska, who now moves up to third.
Tournament director David Brewer had earlier announced Sharapova's withdrawal.
"We wish her a speedy recovery and look forward to her return to New York next year," he said in a statement.