Djokovic, who has advanced to the finals each of the last four years hoisting the title in 2011, plays his first-round match against unseeded Argentine Diego Schwartzman but the Serb must navigate an increasingly trickier path.
The world number one figures to meet either 2012 champion Andy Murray or the on-form Frenchman Jo-Wilfried Tsonga in the quarter-finals.
Federer, winner of five consecutive US Open titles from 2004, opens against Australian Marinko Matosevic.
The second seeded Swiss, aiming to add to his record haul of 17 majors at the advanced age of 33, figures to have a fairly easy ride to a quarterfinals clash against seventh seed Grigor Dimitrov of Bulgaria, nicknamed "Baby Fed" for his versatile game.
On the women's side, two-time defending champion and top seed Serena Williams also looks to have drawn a stern test with former US champion Sam Stosur of Australia a possible fourth-round opponent and eighth seed Ana Ivanovic projected for the quarters.
Williams, who has endured a disappointing grand slam season so far, said she was keen to end on a high note and add to her career haul of 17 major singles titles.
"I feel good. I feel like I'm playing really well," said Williams, who looked fit and glamorous with long, blonde curls framing her face in an appearance at the draw.
"The way my year has gone, I'm worried about every single match," she said when asked to evaluate her draw.
Second seed Simona Halep of Romania opens against American wild card Danielle Rose Collins with a possible clash against Venus Williams in the fourth round.
The other projected fourth-round match in Halep's quarter would have French Open champion Maria Sharapova against former number one Caroline Wozniacki of Denmark.
DJOKOVIC JOUSTS
The top half of the men's draw has third seeded Swiss Australian Open winner Stan Wawrinka on a collision course to face the thundering serves of fifth-seeded Canadian Milos Raonic in the round of eight.
On the women's side, the other quarter of the top half is also loaded with upset-minded players and could offer an early sequel to the Wimbledon final.
Third-seed Wimbledon champion Petra Kvitova of the Czech Republic is projected to face seventh seed Canadian Eugenie Bouchard in the quarters in a rematch of their All England Club final.
Other dangerous players in that bracket include twice US winner Svetlana Kuznetsova and former number one Victoria Azarenka of Belarus threatening to upset the form chart.
