Twenty-four asylum-seekers held on Manus Island off mainland Papua New Guinea flew to Manila en route to an undisclosed American location, the US embassy in Port Moresby told AFP.
"They're the first group that have been approved, that have gone through the extreme vetting process and have met all the requirements for resettlement," said the embassy's public affairs officer Beverly Thacker.
About another 30 refugees held on Nauru in the Pacific will head to the US "in the coming days", she added.
Conditions in the camps have been widely condemned by rights groups and medical professionals.
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Thacker did not provide the nationality of the those being transferred and it is not clear how many of those still remaining will qualify for US resettlement.
"We expect that other refugees will be resettled in the coming months. They will all proceed with different time frames, depending on how fast they will get through the process," she said.
The government has tried with little success to relocate the detainees to third countries like Cambodia, or settle them elsewhere in PNG.
When former president Barack Obama was in office, Australian Prime Minister Malcolm Turnbull made a pact with him to accept an unspecified number of the refugees.
Trump blasted it as a "dumb deal" after assuming the presidency, before begrudgingly agreeing to honour it.
Refugee Action Coalition spokesman Ian Rintoul said the refugees were departing with mixed emotions.
"There are indications that there will be further uplifts of people to the US but it is very unclear when that will be.