Williams will take on Sharapova for the 22nd time in their careers; it is Serena who holds the edge with 19-2 in head-to-head.
They have not faced off for three years at the 2016 Australian Open; so it will be a tie to very much look out for.
Both players are in the same half of the draw as Ashleigh Barty; the no.2 seed who takes on Zarina Diyas in the opening round.
Naomi Osaka, despite injury worries will take on Anna Blinkova in the defence of her US Open title; she could face highly touted prospect, Coco Gauff in round three.
Other top ties include Aryna Sabalenka who takes on former two time finalist, Victoria Azarenka. Simona Halep as number four seed has a tough ask in her section; as she has recent Rogers Cup champion Bianca Andreescu and two-time finalist, Caroline Wozniacki.
As well Cincinnati champion, Madison Keys and Elina Svitolina are in the same quarter as the likes of Karolina Pliskova and Johanna Konta; meaning that it is very much one of the toughest US Opens to call in recent years.