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.
