Rafael Nadal got a walkover, Alexander Zverev was marathon man again and the women's fourth seed was sent packing.
There was success for the two remaining Brits in the singles draw, Dan Evans and Johanna Konta.
Here, PA looks back at day four and ahead to day five at the US Open.
Shot of the day
Delicious from Feliciano on his way to victory and a third-round showdown with Daniil Medvedev.
Stat of the day
Of the 22 matches German sixth seed Alexander Zverev has won at grand slam events, 11 have gone to five sets.
Shock of the day
Taylor Townsend, ranked 116 in the world, dumped out Wimbledon champion Simona Halep, the fourth seed, in a third-set tie-break.
Quote of the day
A successful day as both Johanna Konta and Dan Evans reached the third round. Konta took just 54 minutes to steamroller Margarita Gasparyan, reeling off 12 straight games in a 6-1 6-0 win. She will face China's Zhang Shuai. Evans beat 25th seed Lucas Pouille in four sets. His reward? Roger Federer, first up on Arthur Ashe.
Men: Lucas Pouille (25), Dusan Lajovic (27), Benoit Paire (29), Cristian Garin (31)
Women: Simona Halep (4), Petra Kvitova (6), Hsieh Su-wei (29)
Friday's order of play
Arthur Ashe Stadium:
Dan Evans v Roger Federer
Serena Williams v Karolina Muchova
Sofia Kenin v Madison Keys
Novak Djokovic v Denis Kudla
Louis Armstrong Stadium:
Ons Jabeur v Karolina Pliskova
Maria Sakkari v Ashleigh Barty
Stan Wawrinka v Paolo Lorenzi
Elina Svitolina v Dayana Yastremska
Feliciano Lopez v Daniil Medvedev
Johanna Konta v Zhang Shuai