Hewitt, who stunned sixth seed Juan Martin Del Potro in the second round, squandered a 4-1 lead in the fourth set, and a 5-2 advantage in the fifth as Youzhny battled back to seal victory in three hours and 58 minutes.
"It was a great atmosphere," said Youzhny, the 21st seed at Flushing Meadows. "Finally, I was lucky. The crowd was great and gave me the power to beat Lleyton today."
The 32-year-old Australian had looked headed for his first US Open quarter-finals berth since 2006 after he ran through the third-set tiebreaker against an error-prone Youzhny.
Hewitt then broke Youzhny's serve in the opening game of the fourth set and had all the momentum. But the Russian fought back to break Hewitt in the seventh game, then repeated the feat to be serving for the set at 5-4.
Hewitt and Youzhny traded breaks to start the deciding set. The Australian fell heavily on his left elbow, drawing blood and requiring a medical timeout in the fourth game but still managed to get himself to within two points of clinching the match.
But Youzhny showed his resolve and won five consecutive games to seal the match and secure a quarter-finals showdown with top seed Novak Djokovic.
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