The pair have met in four Grand Slam finals but have never played each other at any stage of the tournament in New York, where six-time champion Williams was last champion in 2014 and Sharapova claimed her only Flushing Meadows title in 2006.
This will be their first meeting since the Australian Open quarter-final of 2016.
Williams dominates the head-to-head between the pair, winning 19 of their 22 matches, with Sharapova claiming just two wins, the last of which came in 2004, and a walkover success at Roland Garros last year when a shoulder injury ruled her out of the contest.
Williams just like Sharapova has not been devoid of struggles in recent times.
Williams has had back problems in recent weeks, while Sharapova has been limited to just six matches since January because of a shoulder injury. Nonetheless, Williams is heading into this grand slam shouldering the task of equaling Margaret Court’s record of 24 grand slam title having won 23 aleady
Elsewhere, Top seed and defending champion Naomi Osaka will play Russia’s Anna Blinkova
Britain’s Johanna Konta faces Daria Kasatkina of Russia while Kyle Edmund will play Spain’s Pablo Andujar.
Dan Evans faces Adrian Mannarino of France while Cameron Norrie will take on a qualifier.
Novak Djokovic begins his title defence against Spaniard Roberto Carballes Baena.
In the men’s draw, Spain’s Rafael Nadal will play Australian John Millman while 20-time Grand Slam champion Roger Federer will face a qualifier yet to be named.
Promising 15-year-old Coco Gauff, who beat Venus Williams on her way to reaching the fourth round at Wimbledon last month, will play Russia’s Anastasia Potapova whereas Wimbledon champion Simona Halep will take on a qualifier yet to be listed.
