World number one Djokovic, who won the title at Flushing Meadows in 2011, is the top seed in the tournament, which is missing injured defending champion Rafael Nadal.
Eighth-seeded Murray, the 2012 US Open winner who hasn't won a title since his 2013 Wimbledon triumph, could face dangerous French ninth seed Jo-Wilfried Tsonga in the round of 16.
Meanwhile, second-seeded Roger Federer has a lighter-looking path, with seventh-seeded Bulgarian Grigor Dimitrov his scheduled quarter-final foe.
Two-time defending champion women's champion Serena Williams could find two familiar rivals in her path as she vies for a first Grand Slam title of 2014. World number one Williams is projected to face Serbian eighth seed Ana Ivanovic in the quarter-finals at Flushing Meadows. Although Williams leads their career head-to-head 7-1, former world number one Ivanovic ousted the American in the fourth round of the Australian Open in January.
Williams could find herself up against another player who has managed to get the better of her on a major stage in the round of 16 -- Australian Samantha Stosur. Stosur, unseeded this year, stunned Williams in the 2011 US Open final.
At least Williams doesn't have to worry about a week-one meeting with elder sister Venus, who landed in the bottom quarter of the draw headlined by world number two and second seed Simona Halep and fifth-seeded Russian star Maria Sharapova.
Elsewhere in the women's draw, third-seeded Petra Kvitova and seventh-seeded Eugenie Bouchard were put on course for a quarter-final clash that would be a re-match of the Wimbledon final. Czech Republic's Kvitova routed rising Canadian star Bouchard in that clash to claim her second Wimbledon crown.