Defending champion Andy Murray could face top-seeded Novak Djokovic only in the U.S. Open semifinals, while Rafael Nadal and Roger Federer — who have never played each other at Flushing Meadows — might meet in the quarter-finals.
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.
No. 10 Milos Raonic of Canada is in Ferrer's quarter of the draw, while unseeded Canadian Vasek Pospisil is in with Nadal and Federer.
Thursday's draw for the year's last Grand Slam tournament also set up these possible men's quarter-finals: 2011 champion Djokovic vs. 2009 champion Juan Martin del Potro, No. 3 Murray vs. No. 5 Tomas Berdych, and No. 4 David Ferrer vs. No. 8 Richard Gasquet.
"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."
The potential women's quarter-finals 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.
Bouchard could bump into Serena
Unseeded Canadian Eugenie Bouchard may have to get past Williams to reach the semifinals, while Canada's Aleksandra Wozniak could have to beat Azarenka.
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.
Possible Djokovic vs. Nadal final
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.