Latvian 16th seed Anastasija Sevastova rallied to eliminate the five-time Grand Slam champion 5-7, 6-4, 6-2 at Arthur Ashe Stadium, booking a quarter-final against American Sloane Stephens, who ousted Germany's Julia Goerges 6-3, 3-6, 6-1.
Sharapova, the 2006 US Open winner, was able to find the positives after making 51 unforced errors to only 14 by Sevastova, whose 21 winners were half the 30-year-old Russian's total.
"Reflecting back on the week, I can be happy," said Sharapova. "It has been a really great ride. Ultimately, I can take a lot from this week."
Tuesday's other quarter-final will match Czech 13th seed Petra Kvitova, a two-time Wimbledon champion, against US ninth seed Venus Williams, seeking her eighth Slam title and third US Open crown.
Kvitova eliminated Spanish third seed and two-time Slam winner Garbine Muguruza 7-6 (7/3), 6-3 while Williams beat 35th-ranked Spaniard Carla Suarez Navarro 6-3, 3-6, 6-1.
In Sharapova's first Slam since she tested positive for the banned blood booster meldonium at the 2016 Australian Open, she ousted second-ranked Simona Halep in the first round and served notice to any contender her game remains formidable.
"She played unbelievable throughout the first and second set and I just kept fighting, running for every ball," said Sevastova. "I was confident. I was feeling it. But still you have to beat her. She was playing one of the best matches here."
Sharapova returned from her suspension in April, was snubbed for a French Open wildcard and missed Wimbledon with a thigh injury but received a US Open wildcard despite only one hardcourt tuneup match due to a left forearm injury.
"It's great to get that major out of the way," said Sharapova. "I'm thankful for the opportunity. I did my best and I can be proud of that."
Sharapova is expected to jump from 146th to around 100th in the world rankings.
Williams is the oldest woman entered at 37 but was this year's Wimbledon and Australian Open runner-up. She hasn't reached three Slam finals in a year since 2002.
"I'm focused on myself and trying to be as aggressive as possible," said Williams. "Nobody ever gives you a Slam. You've got to take it and I'm going to try and take it."
COMMENTS
Comments are moderated and generally will be posted if they are on-topic and not abusive.
For more information, please see our Comments FAQ