Shelton will next face defending champion Carlos Alcaraz, and the 23-year-old showed he has the tools to trouble the Spaniard, blending raw power with a delicate touch and sharp decision-making to overwhelm Tsitsipas in an opening set that lasted only 31 minutes on Arthur Ashe Stadium.
"I was focused today," said Shelton, a 2023 US Open semi-finalist. "I played a complete match from start to finish."
"I think the level that he's been playing at is really, really impressive," Shelton said. "I think it's going to be fireworks on Tuesday night."
With a two-set cushion, Shelton sprinkled some showmanship into the clash in the next with a soaring overhead smash before racing away and completing an emphatic win with a comfortable hold of serve.
Shelton is bidding to become the first U.S. man to win a major since Andy Roddick's 2003 triumph at Flushing Meadows.
