Scotsman Murray, who beat Serb Djokovic in an epic five-set final to claim last year's title at Flushing Meadows, was elated to be back at a venue where he has enjoyed considerable success.
"This is a huge tournament for me," Murray, 26, said after the official draw ceremony was completed at the Billie Jean King National Tennis Center.
"I came here for the first time when I was 15. I got to my first grand slam final here, my first grand slam win here and I won the juniors here when I was 17 so I love coming back."
Murray will take on Frenchman Michael Llodra in the opening round while Djokovic launches his title bid against Lithuania's Ricardas Berankis.
Seventh seed Federer has been placed outside the top three for the first time in more than a decade at a grand slam and is drawn to meet in-form Nadal in the quarter-finals.
However, the Spaniard could face a tricky opponent in the previous round where he is scheduled to meet big-serving American John Isner, who Nadal beat in the final of the Western and Southern Open last week.
In other likely quarter-finals, fourth-seeded Spaniard David Ferrer is set to meet Frenchman Richard Gasquet, Djokovic could face sixth seed Juan Martin Del Potro of Argentina and Murray is on course to play fifth-seeded Czech Tomas Berdych.
In the women's singles draw, world number one and defending champion Serena Williams is set to come up against Germany's Angelique Kerber in the last eight but she has two other intriguing opponents potentially lying in wait.
Top seed Williams is scheduled to face fellow American Sloane Stephens in the fourth round, the player who stunningly beat her in this year's Australian Open quarter-finals.
Should Serena overcome that potential hurdle, she could then meet her older sister Venus, who has the chance to advance through Kerber's section of the draw.
However, Serena has no plans to look too far ahead as she sets her sights on winning a 17th grand slam singles title.
"I take every match really seriously," Serena said while sitting next to Murray after the draw ceremony. "I don't look too far in the draw. I just look at each match.
"Every match is going to be a very, very tough competition for me and I will just stay focused on one at a time."
Like Murray, Serena is delighted to be back at Flushing Meadows where she won her first grand slam singles title at the 1999 U.S. Open.
"It's so important for me," the 31-year-old smiled. "I told my Dad, 'I want to win the U.S. Open when I grow up. I want to be able to win this title.'
"The first time I ever won a grand slam was here in Arthur Ashe Stadium so it just has so many great memories. The U.S. Open means everything to me."
Second seed Victoria Azarenka of Belarussia, who beat Serena in Sunday's Cincinnati Open final, has been drawn to meet seventh seed Czech Petra Kvitova in the last eight.
The other potential quarter-finals could see third seed Agnieszka Radwanska of Poland against fifth seed Li Na of China while fourth-seeded Italian Sara Errani is scheduled to play sixth seed Caroline Wozniacki of Denmark.
In the opening round, Serena faces an experienced opponent in Italian Francesca Schiavone, the 2010 French Open champion, while Azarenka comes up against Germany's Dinah Pfizenmaier.
(Reporting by Mark Lamport-Stokes in Los Angeles; Editing by Ken Ferris)