Murray earned his first Grand Slam championship by beating Djokovic in the 2012 U.S. Open final, then added a second by beating the No. 1-ranked Serb in the Wimbledon title match last month. But there can't be a rematch in New York in the final, thanks to Thursday's draw.
"Coming to the U.S. Open last year, I'd never won a Grand Slam. I didn't know if I was ever going to win one," Murray said at the draw ceremony. "A lot of people would say ... like, 'He's good enough to win a Grand Slam. He's going to win one.' But the more finals you lose in, the more you start to doubt yourself and think, 'Is it ever going to happen?' Getting that weight off my shoulders last year was huge."
Play at the year's last Grand Slam tournament begins Monday.
In addition to No. 2 Nadal against No. 7 Federer, a 17-time major champion who has his lowest seeding at the U.S. Open since he was 13th in 2002, the other possible men's quarter-finals are 2011 champion Djokovic versus 2009 champion Juan Martin del Potro, No. 3 Murray versus No. 5 Tomas Berdych, and No. 4 David Ferrer versus No. 8 Richard Gasquet or 10th-ranked Canadian Milos Raonic.
Federer, who owns five U.S. Open titles, and Nadal also were set up for a possible quarter-final at Wimbledon this year, but that never materialized: Nadal lost in the first round, and Federer in the second.
The potential women's quarter-finals at the U.S. Open are No. 1 Serena Williams against No. 8 Angelique Kerber, No. 2 Victoria Azarenka against No. 7 Petra Kvitova, No. 3 Agnieszka Radwanska against No. 5 Li Na, and No. 4 Sara Errani against No. 6 Caroline Wozniacki.
The woman who originally was seeded third in the tournament, 2006 champion Maria Sharapova, withdrew Wednesday because of a right shoulder injury.
Raonic, from Thornhill, Ont., joins Vasek Pospisil of Vernon, B.C., in the men's main draw. Montreal's Eugenie Bouchard and Aleksandra Wozniak of Blainville, Que., are in the main women's draw.
More Canadians could advance to the main draw. Toronto's Sharon Fichman, Stephanie Dubois of Laval, Que., and Frank Dancevic of Niagara Falls, Ont., all won their opening qualifying matches Thursday.
Toronto's Steven Diez and Ottawa's Jesse Levine lost the opening round of qualifying.
Williams' 16 Grand Slam titles include four at the U.S. Open, including last year. Her first-round opponent will be 2010 French Open champion Francesca Schiavone. Williams could play 15th-seeded Sloane Stephens of the United States in the fourth round; Stephens won their Australian Open quarter-final in January.
"I take every match really seriously. I don't look too far in the draw. I just look at the first one," Williams said. "For me, my competition comes with each match. Every match is going to be a very, very tough competition for me, and I just stay focused on one at a time."
Williams has won 77 of her past 81 matches, and was asked Thursday whether she is playing better than she ever has.
"I hope not," Williams answered. "I always like to hope I can do better, so we'll see."
Her older sister, 2000-01 U.S. Open champion Venus, is unseeded and was drawn to play No. 12 Kirsten Flipkens, a Wimbledon semifinalist last month, in the first round next week.
Djokovic and 2010 U.S. Open champion Nadal, who recently overtook Murray at No. 2 in the rankings, could meet only in the final. They've already met in five Grand Slam championship matches, including in New York in 2010 and 2011.
One intriguing earlier matchup for 12-time major title winner Nadal could come in the fourth round, when he might have to play six-foot-10 John Isner, a big-serving American who is seeded 13th and pushed the Spaniard to five sets at the French Open two years ago.
Nadal was drawn to play another American, 21-year-old Ryan Harrison, in the first round.
Djokovic, who has reached at least the semifinals at the U.S. Open each of the past six years, could face 25th-seeded Grigor Dimitrov in the third round. Dimitrov surprisingly beat Djokovic on clay at the Madrid Masters in May, although Djokovic won their matchup less than a month later at the French Open.
In the second round, Djokovic might play Lukas Rosol, the man who upset Nadal at Wimbledon while ranked 100th in 2012, or Benjamin Becker, who defeated Andre Agassi at the 2006 U.S. Open in the American's last professional match.
— With files from The Canadian Press.