The 30-year-old Russian, who ousted second seed Simona Halep in her opener, faces Hungary's Timea Babos.
The 30-year-old Russian, who ousted second seed Simona Halep in her opener, faces Hungary's Timea Babos for the first time in the second round of the year's final Grand Slam tournament.
And with Halep and British seventh seed Johanna Konta both ousted already, Sharapova would not see another top-10 foe until potentially 10th-ranked Dominika Cibulkova in the quarter-finals even as three top-10 foes lurk as possible semi-final rivals.
The draw is wide open for a deep run by Sharapova despite her relative lack of matches and nagging injuries that allowed her only one hardcourt tuneup to the Open.
"From the moment that I've been here, I've really understood what this means to me, to be back and to be playing," Sharapova said.
"Not playing a lot of matches coming into this, it almost seemed like I had no right to (beat Halep). And I somehow did. I think that is what I'm most proud of."
Sharapova served a 15-month doping ban after testing positive for meldonium at the 2016 Australian Open, returning in April to fanfare and controversy.
She missed Wimbledon with a thigh injury after being snubbed for a French Open wildcard but was given a wildcard into the US Open and wants to make the most of it.
"I was obviously extremely excited. I realized how long it had been since I played at the US Open," said Sharapova, who missed three of the prior four New York showdowns.
"Since I've come back, I feel like I'm on a team. I'm not just winning for myself, but I'm winning for everyone that has stood behind me. That is a very special feeling to have."
Applause and support from the crowd at Arthur Ashe Stadium bolstered her confidence and enthusiasm against Halep as she improved to 18-0 in night matches on the main court.
"So much. So special. I felt the support in the States," Sharapova said. "This is obviously a different scale, completely different caliber to anywhere you play in the world. It's electric."
Spanish third-seed Garbine Muguruza, the reigning Wimbledon champion, can reach the US Open third round for the first time by beating China's Duan Ying-Ying.
US ninth seed Venus Williams, this year's Wimbledon and Australian Open runner-up, meets France's Oceane Dodin while Danish fifth seed Caroline Wozniacki faces Russian Ekaterina Makarova.
On the men's side, German 20-year-old fourth seed Alexander Zverev, the top ranked player in his half of the draw, meets Croatian Borna Coric in the second round as he tries to crack the final eight at a major for the first time.
"You have to improve everything a little bit," Zverev said. "Obviously you can't be satisfied after a first-round win. I want to go deeper."