Defending champion Nadal pulled out on Monday due to a wrist injury that forced him to miss the Rogers Cup and Cincinnati Masters last month.
His decision not to compete has seen Federer promoted to second seed behind world number one Novak Djokovic as the Swiss aims to continue his recent resurgence at Flushing Meadows.
A five-time champion in New York, Federer has not won a grand slam since his victory over Andy Murray in the Wimbledon final in 2012, but came close to doing so as he was beaten in five sets by Djokovic at the All England Club in July.
And the Swiss heads into the tournament in great form having reached the final of the Rogers Cup before winning his 80th career singles title in Cincinnati last Sunday.
Murray is seeded eighth as he attempts to repeat the performance that saw him win his maiden grand slam crown at this event in 2012.
However, the Brit will have to find some consistency if he is to go deep into the tournament, with his relatively low seeding reflecting a season in which he has failed to reach the final of any event.
Australian Open champion Stanislas Wawrinka is seeded third ahead of his quest for a second grand slam of the year, while David Ferrer - beaten by Federer in the Cincinnati final - is the fourth seed.
Rising stars Milos Raonic and Grigor Dimitrov are seeded fifth and seventh respectively, with that pair sandwiched by 2012 semi-finalist Tomas Berdych.