The Spaniard overcame Novak Djokovic 12 months ago to claim the title at Flushing Meadows for the second time in his career.
However, he has been plagued by a wrist injury of late, which has not healed in time for him to defend his crown in New York.
"I am very sorry to announce I won't be able to play at this year's US Open a tournament on which I've played three consecutive finals in my last participations. I am sure you understand that it is a very tough moment for me since it is a tournament I love and where I have great memories from fans, the night matches, so many thing," the 28-year-old wrote on his official Facebook page.
"Not much more I can do right now, other than accept the situation and, as always in my case, work hard in order to be able to compete at the highest level once I am back."
The tournament gets underway next Monday.