By Steve Keating
Always a crowd favorite at Flushing Meadows, Williams will have to share some of cheers as she goes against fellow American Vania King in a second round matchup.
Williams may be a big fan of the next generation of American players but for the second successive match the 17-time grand slam winner will do her best to usher another compatriot to the exit having dismissed Taylor Townsend in the opening round.
"I'm not sure if I played her (King) before but I've always liked her game," said Williams, who will also join big sister Venus in the doubles on Thursday. "She gets a lot of balls back.
"She likes to hit lots of rallies. She's another American. So it's a shame that Americans have to keep playing each other. But, hey, at least an American can go to the third round."
Djokovic, who has reached the Flushing Meadows final each of the last four years, got his U.S. Open campaign off to an impressive start with a straight sets win over Argentine Diego Schwartzman and will meet Frenchman Paul-Henri Mathieu in the second round.
"It's not the first time and hopefully not the last time that I'm first seed," said Djokovic. "It's definitely a privilege and responsibility.
"Pressure is part of the sport. I'm used to it already. I enjoy pressure in a way because it brings meaning to what I do. It definitely motivates me more."
While Djokovic and Williams will dominate the spotlight there will be plenty of big names in action all across the sprawling tennis complex.
Eighth seeded Briton Andy Murray, the 2012 U.S. Open champion, takes on Germany's Matthias Bachinger before seventh seeded Canadian Eugenie Bouchard wraps up the Arthur Ashe Stadium program against Romania's Sorana Cirstea.
Two of tennis's big-hitters will try to blast their way into the third round with fifth seeded Canadian Milos Raonic facing Germany's Peter Gojowczyk while American 13th seed John Isner meets Germany's Jan-Lennard Struff.
(Editing by Greg Stutchbury)