The suspects, 16 and 22, were being held on suspicion of murdering Aubrey Sacco, who disappeared in April 2010 and has never been found, CNN reported Saturday.
Sacco, 23, from Colorado, had been hiking alone in the same region the suspects are from about 60 miles north of Kathmandu.
"We assume that she has been murdered," police said in announcing the arrests.
Sacco's father and two other people flew to Nepal after she vanished in the Langtang National Park. They interviewed locals who said if they knew anything, they would not tell authorities.
The Saccos left the country with "no leads, no evidence of any sort," said Connie Sacco, Aubrey's mother.