Seven carriages including the engine of the Amtrak train bound for New York went off the track on Tuesday evening.
Part of the US’s most travelled stretch of passenger rail between Philadelphia and New York was closed as officials tried to determine the cause.
More than 240 people were on board Train 188, officials said.
The National Transportation Safety Board said it was dispatching a team of investigators to the crash site on Wednesday.
Rescue workers continued to search through the wreckage on Wednesday in search of more victims.
The train derailed in a suburb of Philadelphia, shortly after leaving the city’s main station.
At least eight of the victims were listed as being in a critical condition at local hospitals.
“It is a devastating scene,” Philadelphia Mayor Michael Nutter told reporters. “Never seen anything like this in my life.
“We walked the entire length of the train area. The engine [is] completely separated from the rest of the train and one of the cars is perpendicular to the rest of the cars. It’s unbelievable.”
Television pictures from the scene showed injured passengers being taken away on stretchers and firefighters using ladders to search for those trapped in wreckage.
Many others appeared to have minor injuries.
Daniel Wetrin, was among more than a dozen people taken to a nearby elementary school afterwards.
“I think the fact that I walked off (the train) kind of made it even more surreal because a lot of people didn’t walk off,” he said. “I walked off as if, like, I was in a movie. There were people standing around, people with bloody faces. There were people, chairs, tables mangled about in the compartment … power cables all buckled down as you stepped off the train.”
Patrick Murphy, a former US congressman, tweeted that he was on the train when it crashed.
“Im on @Amtrak train that just crashed. Im ok. Helping others. Pray for those injured,” he wrote.
Associated Press employee Paul Cheung said he was fortunate to be at the back of the train and the front of it “looks pretty bad”, the news agency reported.
He said just before the crash the train “started to decelerate, like someone had slammed the brake”.
“Then suddenly you could see everything starting to shake.. You could see people’s stuff flying over me.”
Mr Cheung added that the front of the train was “a complete wreck. The whole thing is like a pile of metal”.
The crash took place close to the scene of one of the worst rail accidents in US history. In 1943, 79 people were killed when a train travelling from Washington to New York derailed.
Amtrak is a national publicly funded rail service, serving tens of millions of people every year.