The Swiss maestro will face lefty Feliciano Lopez, who may have his best chance yet to score a victory after falling to Federer is all 12 of their previous meetings.
The 36-year-old Federer is apparently still suffering from the back pain that kept him out of the Cincinnati Masters and needed five sets to dispatch his first and second round opponents.
World number one Rafael Nadal will battle big-hitting Argentine Leonard Mayer in his third round match on Arthur Ashe and, like Federer, will hope to improve on his less-than-dominant performances thus far in the final grand slam tournament of the year.
Fans will also be treated to a grandstand battle between stalwarts Roberto Bautista Agut of Spain and 2009 champion Juan Martin del Potro of Argentina.
On the women's side, top-seeded Karolina Pliskova will kick off the action at Arthur Ashe Stadium when she faces 27th-seeded Shuai Zhang of China.
Two American women will also try to punch their tickets to the fourth round.
CoCo Vandweghe will look to continue her excellent tournament play when she faces 10th-seeded Pole Agnieszka Radwanska prior to Nadal's match.
Fifteenth-seeded Madison Keys will battle 17th-seeded Russian Elena Vesnina under the bright lights of Arthur Ashe Stadium to close the day down.
(Reporting by Rory Carroll; editing by Ralph Boulton)
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