Murray, who is also the Wimbledon champion, landed in the top half of the draw for the August 26-September 9 tournament in New York while second seed Rafa Nadal and five-times U.S. Open champion Roger Federer were placed in the bottom half.
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," he said.
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.