World number one Roger Federer will begin his bid to win a record sixth consecutive US Open against American wildcard Devin Britton after the draw was made on Thursday.
The Swiss, who won the French Open and Wimbledon titles this year to set a record of 15 Grand Slam singles victories, is scheduled to play fourth seed Novak Djokovic of Serbia in the semi-finals.
If Federer wins the title he will match Bill Tilden's six straight victories in the US tennis championships during the 1920s before the event was open to professionals.
Women's champion Serena Williams begins her campaign against American wildcard Alexa Glatch.
"I am still playing very well," Federer said at the draw. "I played great in Cincinnati [where he won the Masters Series event last weekend] and I hope things can go well at the U.S. Open."
Second seed Andy Murray, runner-up last year and chasing his first Grand Slam crown, could face third seed Rafael Nadal in the semi-finals.
NADAL OPENER
Scot Murray will begin against Latvian Ernests Gulbis while Spaniard Nadal, who missed Wimbledon because of tendinitis in his knees, takes on Frenchman Richard Gasquet in one of the highlights of round one.
Fourth seed Djokovic will play Croatian Ivan Ljubicic and former champion Andy Roddick, the leading American seed at number five, takes on Bjorn Phau of Germany in round one.
Djokovic and Roddick are seeded to face each other in the quarter-finals.
In the women's event, Williams is seeded two behind world number one Dinara Safina and could face her sister Venus, the third seed, in the semi-finals.
Russian Safina, still chasing her first Grand Slam title, plays Australian wildcard Olivia Rogowska in the opening round while Venus takes on another Russian Vera Dushevina.
Former champion Maria Sharapova, seeded 29, starts against Bulgarian Tsvetana Pironkova and could face fourth seed Elena Dementieva in round three.
Belgian former world number one Kim Clijsters, who returned to the tour this month after a two-year layoff, will play Viktoriya Kutuzova of Ukraine in round one.
The 2005 champion could play Venus Williams in the fourth round.
The US Open begins on Monday.
