Five-times U.S. Open champion Federer will start a warm favourite, but will take nothing for granted when he takes to the Arthur Ashe Stadium court against the 13th seed for the final match of the night.
Federer has a 4-1 career record against Isner.
Also on Monday, third seed Andy Murray continues his quest for a second U.S. Open title when he meets Kevin Anderson.
South African Anderson, the 15th seed, has been in good form, winning a small lead-up tournament in North Carolina on his way to New York.
Fifth seed Stan Wawrinka gets a matchup with American comeback kid Donald Young, who has twice erased two-set deficits to advance.
Czech Tomas Berdych faces off with Frenchman Richard Gasquet in the other fourth-round match.
On the women’s side, second seed Simona Halep will be tested by 24th seed Sabine Lisicki, while 97th ranked Johanna Konta goes for her third straight upset when she takes on fifth seed Petra Kvitova.
Czech Kvitova has rounded into sizzling form at the right time, winning the Connecticut Open last week.
(Reporting by Jahmal Corner in Los Angeles. Editing by Andrew Both)
