Federer, the second seed, takes on Australian John Millman in the last 16 in the day’s final match at the Arthur Ashe Stadium, while sixth seeded Djokovic faces unseeded Portuguese Joao Sousa in the day session.
Federer won his only other career meeting with Millman in three sets in Brisbane three years ago while Djokovic, the Wimbledon champion, has never lost to Sousa in four meetings.
The first time the Serb met Sousa was at the 2013 U.S. Open, where he won in straight sets, a pattern that has been repeated in each of their three subsequent encounters.
Seventh seed Marin Cilic, who came through a marathon five-setter against Australian teenager Alex de Minaur on Saturday, resumes his quest for a second US Open crown against Belgian 10th seed David Goffin.
In women’s action, last year’s runner-up Madison Keys opens on Arthur Ashe against Slovakian 29th seed Dominika Cibulkova.
A fifth consecutive career victory over Cibulkova will see Keys meet either Maria Sharapova or Spaniard Carla Suarez Navarro in the quarter-finals.
Russian Sharapova, the 2006 champion, has had three straight sets victories so far and has only ever lost one of her five previous meetings with Suarez Navarro.
Sharapova kicks off the evening session on Arthur Ashe, having never lost any of her 22 night matches in New York.
US Open order of play
Arthur Ashe Stadium
12:00: (14) Madison Keys (USA) v (29) Dominika Cibulkova (Svk), (6) Novak Djokovic (Ser) v Joao Sousa (Por), (30) Carla Suarez Navarro (Spa) v (22) Maria Sharapova (Rus), John Millman (Aus) v (2) Roger Federer (Swi)
Louis Armstrong Stadium
11:00: (21) Kei Nishikori (Jpn) v Philipp Kohlschreiber (Ger), (26) Aryna Sabalenka (Blr) v (20) Naomi Osaka (Jpn), (7) Marin Cilic (Cro) v (10) David Goffin (Bel), Nadiia Kichenok (Ukr) & Wesley Koolhof (Ned) v Bethanie Mattek-Sands (USA) & Jamie Murray (Gbr)
Grandstand
11:00: (5) Juan Sebastian Cabal (Col) & Robert Farah (Col) v (11) Ivan Dodig (Cro) & Marcel Granollers (Spa), (4) Jamie Murray (Gbr) & Bruno Soares (Bra) v (14) Robin Haase (Ned) & Matwe Middelkoop (Ned), Marketa Vondrousova (Cze) v Lesia Tsurenko (Ukr)
Court 5
11:00: Shuai Zhang (Chn) & John Peers (Aus) v (2) Nicole Melichar (USA) & Oliver Marach (Aut)
Court 17
11:00: (15) Rohan Bopanna (Ind) & Edouard Roger-Vasselin (Fra) v Jeremy Chardy (Fra) & Fabrice Martin (Fra), (3) Andrea Sestini Hlavackova (Cze) & Barbora Zahlavova Strycova (Cze) v (13) Ashleigh Barty (Aus) & Coco Vandeweghe (USA), Anastasia Pavlyuchenkova (Rus) & Anastasija Sevastova (Lat) v Caroline Dolehide (USA) & Christina McHale (USA), Su-Wei Hsieh (Tpe) & Aryna Sabalenka (Blr) v (7) Elise Mertens (Bel) & Demi Schuurs (Ned)