The top seeds in the men’s and women’s singles are both in action during the evening session on Arthur Ashe Stadium.
Poland’s Iga Swiatek is yet to drop a set in the tournament and goes up against 16th seed Liudmila Samsonova at 00:00 BST.
That is followed by Italy’s Australian Open champion Jannik Sinner taking on American 14th seed Tommy Paul.
Sixth seed Jessica Pegula of the United States opens play on the main showcourt against Russia’s Diana Shnaider.
Daniil Medvedev, the only former New York champion left in the men’s singles draw, then faces Portugal’s Nuno Borges.
On Louis Armstrong, Wimbledon finalist Jasmine Paolini takes on fellow French Open runner-up Karolina Muchova.
Former world number one Caroline Wozniacki faces 22nd seed Beatriz Haddad Maia before an all-Australian clash between 10th seed Alex de Minaur and Jordan Thompson in the men’s singles.
There is also plenty of British interest in the doubles with Joe Salisbury and American partner Rajeev Ram continuing their bid for a fourth successive title in the men’s doubles.
Henry Patten and Finn Harri Heliovaara, the Wimbledon champions, are also in action, as are eighth seeds Neal Skupski – another British former Wimbledon doubles winner – and New Zealander Michael Venus.
Olivia Nicholls and partner Tereza Mihalikova of Slovakia proceed Skupski and Venus on Stadium 17 in the women’s doubles.
Harriet Dart and French team-mate Diane Parry are first up on court five.