Del Potro, the 2009 champion at Flushing Meadows, underwent wrist surgery in March, and has not played a competitive match on the ATP World Tour since February.
The Argentine, 25, is still ranked 11th despite his inactivity, and remains on the entry list to compete at the Malaysian Open in late September.
World number 88 Simone Bolelli of Italy is the beneficiary of Del Potro's withdrawal, taking his spot in the main draw as a direct entry.
Bolelli was forced to qualify for both the French Open and Wimbledon in 2014, reaching the second and third rounds respectively at the majors.