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 6-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.
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