Both play unseeded opponents in the round of 16 Monday at Arthur Ashe Stadium. Federer is a five-time U.S. Open champion and Djokovic has won the tournament twice. Djokovic is 27-0 in the U.S. Open against players ranked outside the top 50.
Federer, the No. 2 seed, faces 55th-ranked John Millman. Djokovic, the No. 6 seed, takes on 68th-ranked Joao Sousa. Neither Millman nor Sousa has reached the final eight at a Grand Slam tournament.
There are two other big matches at Ashe when 2006 champion Maria Sharapova plays No. 30 Carla Suarez Navarro, and 2017 runner-up Madison Keys takes on No. 29 Dominika Cibulkova.