It is the fourth grand slam in succession that the pair have been seeded to meet in the semi-finals, with Nadal having already beaten Murray in the French Open and Wimbledon.
Robin Soderling is Murray's scheduled quarter-final opponent in New York, but Juan Martin Del Potro is also lurking in the section.
Murray will first have to see off world number 64 Somdev Devvarman, of India, in the first round, a player he has not met before but one who won the Commonwealth Games gold medal in 2010.
Nadal, who opens against Andrey Golubev, is seeded to meet David Ferrer, the fifth seed, in the last eight.
On the other side of the draw, top seed Novak Djokovic is on course for a last-four meeting with five-time winner Roger Federer.
That would be a repeat of last year's semi-final which Djokovic won after saving two match points.
Federer could first have to overcome in-form American Mardy Fish in the quarter-finals, while Djokovic is on course for a last-eight meeting with Gael Monfils.
The world number one plays a qualifier first up while Federer meets Santiago Giraldo.