The 23-year-old fell 7-6 (6) 6-1 4-6 7-5 to Spain's Tommy Robredo after a tense three and a quarter hour battle at Flushing Meadows.
Evans, ranked 179th in the world, had captured the imagination of New York after his unlikely run to the third round but faltered just when it seemed he was on the verge of claiming another big scalp.
"I'm not disappointed, to be honest, it was a great experience," Evans said.
He had already pulled off the biggest upset of the opening round when beat Japan's Kei Nishikori, ranked 11th in the world, and followed that up by beating Bernard Tomic in the second round.
His win over Tomic was all the sweeter because the Australian's father had once prevented Evans from practising with his son, telling him he was not good enough.
Evans said he used that as motivation and now wants to use his success in New York to improve his ranking.
"It was a good stepping stone but not I'm not where I want to be, in the top 100," he said. "So I've still got a bit of work to do."
Robredo, an experienced campaigner who has been on the grand slam circuit for more than a decade, was always going to be a tough opponent for Evans and the Spaniard looked to be cruising to victory after winning the first two sets.
But the 19th seed began to struggle in the third set because of a leg injury that required medical treatment and had to be iced at each change of ends.
Evans won the third set and had two set points on his own serve in the fourth and the crowd on his side at Louis Armstrong Stadium.
Then the wheels suddenly came off. He served two double faults and Robredo reeled off the last four games in a row to seal victory.
"You just have to learn from these experiences," said Evans. "I don't know what happened. I didn't feel tight, I just missed some easy hits."
(Reporting by Julian Linden; editing by Nick Mulvenney)
