A report in the Baltimore Sun said an explosion was felt several kilometres away.
About 15 cars derailed shortly after 2pm local time near White Marsh, Maryland, and caught fire, sending a thick column of black smoke into the air, TV pictures showed.
The Baltimore County Police and Fire Department said on its Twitter feed that the train was carrying non-toxic chemicals when it hit a tractor-trailer.
The truck's driver was sent to a Baltimore shock trauma centre in serious condition. Two CSX workers on the train were unhurt, it said.
A police and fire spokeswoman said people were advised to leave a nearby 20-block area, with those staying behind urged to keep windows closed and air conditioners off.
An attempt to reach CSX for comment was not immediately successful.
It was the third significant rail crash in the United States in the past two weeks. On Saturday, two freight trains operated by BNSF Railway Co and Union Pacific Corp crashed at a rail intersection in rural Missouri, injuring seven people.
That accident came a little more than a week after a Metro North commuter train derailed near Fairfield, Connecticut. That accident injured more than 70 people and shut down traffic on one of the most heavily traveled passenger rail corridors in the United States.
On Friday, an interstate highway bridge in a rural part of Washington state collapsed after a truck carrying a large load hit a support beam. The collapse sent vehicles and drivers tumbling into a frigid river.
