Federer, who has been in sizzling form since reaching the Wimbledon finals, will face Germany's Philipp Kohlschreiber at Arthur Ashe Stadium, having steamrolled through his first two matches.
"Very often I start this tournament quite strong," the 34-year-old Swiss said after crushing Belgium's Steve Darcis 6-1 6-2 6-1 in the second round.
"It's always gone quite well for me. I've always enjoyed conditions here -- the balls, the speed of the court, the atmosphere in the arena. I think this is another good year."
Also in action on Saturday will be third-seeded Scot Andy Murray and fifth seed Stan Wawrinka of Switzerland.
Murray, who won his first grand slam title at the 2012 U.S. Open, plays against Brazil's Thomaz Bellucci while Wawrinka takes on Belgian Ruben Bemelmans.
In the women's championship, fifth-seeded Czech Petra Kvitova launches proceedings at Arthur Ashe Stadium against Slovakia's Anna Karolina Schmiedlova before second seed Simona Halep of Romania faces American Shelby Rogers in an evening match.
(Reporting by Mark Lamport-Stokes in Los Angeles; Editing by Steve Keating)
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