The French Open champion has never found the same success on the Flushing Meadows hard courts as she has on Parisian clay, where she claimed her first grand slam title in May by beating Serena Williams in the final.
In four visits to the U.S. Open, the 22-year-old has yet to advance to the third round in New York and the Spaniard was unable to overcome her 48th-ranked opponent this time in a sloppy contest littered with service breaks.
Muguruza came into the year's final grand slam with a chance to usurp Serena Williams at the top of the world rankings if she could win the tournament, but she was already claiming it would need "a miracle" to even reach the final after her first match.
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The Spaniard, however, did not go down without a fight.
Serving for a third round berth at 5-1, Sevastova had two match points but could failed to convert either as Muguruza registered the break to keep her hopes alive.
Muguruza continued to close the gap by holding to love then breaking the crumbling Latvian a second time to get the set back on serve.
With the match slipping away and the crowd at the massive Arthur Ashe Stadium court buzzing, Sevastova calmed her nerves to break once more, sealing the biggest win of her career with a fizzing forehand crosscourt winner.
LITANY OF ERRORS
"I was shaking a little bit at the end," the 26-year-old Sevastova admitted in an on-court interview. "A night match on Ashe. What is going to be bigger?
"I thought, 'Why do they put me on Ashe at 7 p.m.?' I mean, I think they thought it should be a good match.
"It feels great, but it's still not like I won the tournament. It's only second round."
It was certainly not the high quality match one might have been expected to see at prime time on one of the sport's biggest stages, Sevastova committing a whopping 34 unforced errors but outdone by an even sloppier Muguruza with 38.
Muguruza did take a majority of her chances, converting five-of-six break point opportunities, but Sevastova was able to capitalise on seven of the 12 the Spaniard presented to her in the error-prone contest.
While Muguruza needs to go back to the drawing board, the victory could serve as a key stepping stone in Sevastova's rehabilitation after the Latvian retired in May 2013 due to a chronic run of injuries before launching a comeback last year.
"I think I had to work on it when I took the time off," said Sevastova, who will face Ukraine's Kateryna Bondarenko in the third round. "I think I manage it better now that I stay in the moment. It's tough to not look ahead.
"We can enjoy it today but tomorrow is a new day. You have to think forward."
(Editing by John O'Brien)
