"Juan Martin Del Potro has just withdrawn. It is very unfortunate. I am sure he is disappointed not to be able to defend his title but we look forward to seeing him in New York next year," Chris Widmaier, USTA's managing director of communications, said at the current ATP tournament in Cincinnati on Saturday.
Del Potro has not played since January 24, when he lost to Croatian Marin Cilic at the Australian Open.
In May, he underwent surgery for a persistent wrist problem and only recently returned to hitting balls.
"I feel extremely sad to announce that I will not to be able to defend my US Open title," the 21-year-old Del Potro said in a statement.
"Winning in New York last year has been my major accomplishment in tennis and my best memory so far.
"I am so sorry for my fans, my sponsors and all the people that care about me, but I have only started practising in the last two weeks and unfortunately I cannot compete at the top level yet.
"I look forward to returning to New York in 2011 and wish all the best to the tournament organisers and my fellow players."
US Open Tournament Director Jim Curley said in a statement issued through USTA: "It is unfortunate that Juan Martin has not recovered from wrist surgery in time to defend his US Open title. We wish him all the best and look forward to his return to New York next year."
Del Potro won his first Grand Slam title by rallying to beat five-time US Open champ Roger Federer in five sets in last year's final at Flushing Meadows.
Del Potro's withdrawal comes the day after women's world number one Serena Williams pulled out of the women's event at the US Open because she is still recovering from surgery to repair cuts on her right foot.
The US Open begins August 30.