Around 141 passengers and 16 crew were traveling from Chicago toward the Pacific coast when eight of the 10 cars came off the tracks at around 16:00 (22:00 GMT).
“We are deeply saddened to learn local authorities are now confirming that three people have lost their lives as a result of this accident,” rail operator Amtrak said, adding that there were also “reported injuries”.
It was not immediately clear what caused the incident.
Footage posted on social media showed people waiting by the tracks, luggage strewn next to them, with train carriages seen listing off the rails and at least one toppled onto its side.
The National Transportation and Safety Board said it was launching a “go-team” to investigate the derailment.
Amtrak said it had sent emergency personnel to the scene to assist local authorities in the evacuation effort.
Montana’s Disaster and Emergency Services coordinator Amanda Frickel told the New York Times that “well over 50 people had been injured”.
She said teams of rescuers were at the scene and multiple hospitals – as well as medical helicopters – were on standby.
Authorities were not releasing further details for the time being, she said, adding: “Everybody who is alive has been extricated from the wreck.”
The Empire Builder train derailed in a remote area near Joplin, Montana, a town of around 200 people near the border with Canada.
Montana Senator Jon Tester said he was monitoring the derailment.
“My thoughts are with all the passengers, crew, and first responders on the scene,” he added.
Amtrak said it was cancelling some trains on Saturday between the states of North Dakota and Montana, and abridging two Empire Builder train services on Sunday, with no substitute transit available.
The US rail network suffers from chronic underfunding and fatal accidents sometimes occur.
In 2018, two people died in South Carolina when an Amtrak train traveling on the wrong tracks collided with a stationary freight train, in a crash later blamed on safety oversights.
A year earlier, an Amtrak passenger train traveling on a new route for the first time derailed in Washington state, killing at least three people as cars plunged off a bridge onto a busy highway at the height of morning rush hour.
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