It was not immediately clear how many people were hurt beyond the three people who died, the Missouri State Highway Patrol said.
At least eight medical helicopters responded from around the state, Matt Daugherty, Lifeflight Eagle director of business development, told The Kansas City Star.
He said he knew there were a number of injuries and some people were in a critical condition.
The Southwest Chief was carrying about 243 passengers and 12 crew members when the collision happened near Mendon on Monday afternoon, rail company Amtrak said.
The Highway Patrol said seven cars derailed.
Helicopter video shown by KMBC-TV in Kansas City from the scene showed rail cars on their side as emergency responders used ladders to climb into one of them.
The video also showed six medical helicopters parked nearby waiting to transport patients.
Passengers on the train included high school students from Pleasant Ridge High School in Easton, Kansas, who were headed to a Future Business Leaders of America conference in Chicago, Superintendent Tim Beying told The Kansas City Star.
Mendon, with a population of about 160, is about 135 kilometres northeast of Kansas City.
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