Police say there were "multiple" fatalities on board the train, which hit vehicles on the I-5 highway below.
Images from the scene show that all the carriages of the high-speed train appear to have left the track.
It was Amtrak's first passenger service to run on a new, shorter route.
Train 501 had left Seattle, heading south for Portland, at 06:00 local time (14:00 GMT). The derailment happened on a section of track, south of Tacoma, previously only used for freight trains.
Reports suggest 77 people have been taken to hospital.
Several cars on the highway were struck by the derailed carriages. Aerial images show the train's carriages littered across the ground, on both sides of the bridge carrying the railway over the motorway.
Pierce County Sheriff's department spokesman Ed Troyer said there were "multiple" fatalities on the train but no motorists had been killed.
The fire department had taken many people out of the train and they had been transported to hospitals, he added.
President Donald Trump's first reaction to the derailment was to tweet that it showed the need for his forthcoming infrastructure plan.
He later added that his thoughts and prayers were with those involved.
Washington's governor has declared a state of emergency in two counties.
Passenger Chris Karnes, on board the train, said his carriage had careened down an embankment then come to a stop: "We could hear and feel the cars crumpling and breaking apart, and water came out from the ceiling."
"In order to get out... we had to kick out the emergency window," he added.
Amtrak said approximately 78 passengers and five crew members had been on board the train.
Governor Jay Inslee said he was praying for the many injured.
Officials have set up a family reunification centre at DuPont city hall, and asked people not to come to the scene of the crash.
The National Transportation Safety Board is investigating.