Officials confirmed the Osprey vertical takeoff aircraft had been carrying US "defence personnel", with local media reporting that around 20 people were on board at the time.
The Care Flight rescue service told AFP that three passengers had been rushed to Darwin Hospital -- with one of them in a critical condition and the other two stable.
"At this critical early stage, our focus is on the incident response and ensuring the safety of those involved," the Defence Department said in a statement, adding that Australian soldiers were "not involved".
An emergency services incident map for the Northern Territory said there had been an "aircraft crash" on Melville Island, located some 60 kilometres (37 miles) north of the Australian mainland in the eastern Timor Sea.
The Osprey was taking part in the Predators Run exercises, a joint series of warfighting drills involving thousands of soldiers from the US, Australia, and other militaries such as Indonesia and the Philippines.
Northern Australia has become an increasingly important staging ground for the US military in recent years, as the two allies look to counter China in the Asia-Pacific region.
- Troubled aircraft -
Ospreys are tilt-rotor aircraft that combine the features of both helicopters and turboprop planes, according to the US Air Force.
The hybrid craft has two swivelling engines positioned on fixed wingtips that allow it to land and take off vertically, but also travel much faster than a conventional helicopter.
The Osprey aircraft's safety record has repeatedly come into question after a series of fatal incidents.
In April 2000, 19 Marines were killed when an Osprey crashed during a training exercise in Arizona.
And three marines were killed in 2017 when an Osprey crashed after clipping the back of a transport ship while trying to land at sea off Australia's north coast.
In July, four Australians died when their Taipan helicopter plunged into the sea during a separate series of multinational war games near Queensland.
The Taipan had been taking part in the large-scale Talisman Sabre exercise, which brought together 30,000 military personnel from Australia, the United States and several other nations.
It crashed near the Whitsunday Islands while taking part in a nighttime operation.
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