Next Serena will face 22nd seed Petra Martic. Wimbledon quarter-finalist Muchova held serve for an early 3-2 lead in her first career meeting with Williams but the six-times champion cranked up the pace and won the next seven games to take over the match.
Meanwhile second seed Ashleigh Barty saw off 30th seeded Greek Maria Sakkari 7-5 6-3 to set up a last 16 encounter with Chinese hopeful Qiang Wang who beat Fiona Ferro in straight sets.
Briton Johanna Konta reached the last 16 in the Big Apple for the third time in her career and first since 2016 after easing past China’s Shuai Zhang 6-2 6-3. Next up for Konta is third seed Karolina Pliskova of the Czech Republic, who needed three sets to get past Tunisian Ons Jabeur.
Australian next gen star Alex de Minaur progressed to his maiden Grand Slam last 16 showing after upsetting seventh seeded Kei Nishikori in four sets. de Minaur booked an encounter against either Bulgarian Grigor Dimitrov or Poland’s Kamil Majchrzak, both of which are unseeded. Stan Wawrinka beat Italian Paolo Lorenzi in straight sets after a match lasting more than three hours and two tie-breakers.