The world number two announced on Wednesday that he will miss the upcoming ATP 1000 Rogers Cup and Cincinnati Masters tournaments due to a right wrist problem sustained in practice.
As such, he relinquishes his titles at both of the premier warm-up events for Flushing Meadows.
But of more concern to Nadal will be the fact he has been advised to miss a minimum of 14-21 days of competitive action - meaning he may face a race against time to be ready for the fourth and final grand slam of the year, which gets under way in New York on August 25.
In a statement, the 14-time slam winner said: "Unfortunately, I injured my right wrist yesterday during practice and after the tests I have undergone today in Spain, including an MRI, and checking with my doctors, I will have to stay out of competition for at least two to three weeks.
"I am extremely disappointed that I am unable to defend my titles and compete in Toronto and Cincinnati this year.
"I was looking forward to coming and playing again after my great results last year."
Toronto and Cincinnati provided the ideal preparation for Flushing Meadows for Nadal in 2013, as he beat Milos Raonic and John Isner in the finals before going on to defeat Novak Djokovic to claim his second US Open crown.