Open as the 2009 champion continues to recover from a knee injury, tournament organisers said on Tuesday.
The Argentine re-fractured his kneecap during the Queen's Club Championships in June in the latest setback to his injury- plagued career.
The world number 12 missed Wimbledon after scans revealed he had fractured his right patella and he underwent surgery.
Since his triumph at Flushing Meadows Del Potro, 30, has had three left wrist surgeries and another to his right wrist but he has fought back each time to return to the tour.
He reached last year's U.S. Open final and won the 2018 Masters 1000 event at Indian Wells but has said the knee injury could mean the end of his career.
Del Potro will be replaced in the main draw at Flushing Meadows by American Denis Kudla.
(Reporting by Rory Carroll)