Serena Williams' matchup against 17-year-old American Caty McNally heads a lineup of second-round contests that similarly pit established champions against hungry upstarts.
The eighth-seeded Williams, a 23-time Grand Slam singles champ, will be heavily favored in the nightcap in Arthur Ashe Stadium against McNally, who is ranked No. 121 and got her first victory in a Grand Slam event after receiving a wild card to play singles and doubles with fellow teenage star Coco Gauff.
Defending men's champ and top seed Novak Djokovic is in the leadoff night match in Ashe, taking on 56th-ranked Juan Ignacio Londero after third-seeded Roger Federer plays 99th-ranked Damir Dzumhur.
Other key matches on Wednesday include Venus Williams against No. 5 Elina Svitolina, and No. 2 Ash Barty taking on 73rd-ranked American Lauren Davis.