Up to 10 carriages of the Washington-New York Amtrak service went off the track on May 12.
Emergency officials and fire-fighters are at the scene looking for passengers who may be trapped in the wreckage.
More than 240 people were on board Train 188, officials say.
It is not known what caused the derailment.
The National Transportation Safety Board said it was dispatching a team of investigators to the crash site.
The train derailed in a suburb of Philadelphia, shortly after leaving the city’s main station.
Philadelphia Mayor Michael Nutter said at least five people died.
“It is a devastating scene,” 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.”
The mayor also said that, according to preliminary information, 243 people were on the train. Not all had been accounted for, he said.
A fire official was quoted as saying that more than 50 people were taken to hospital, six of them critically injured.
TV footages from the scene showed injured passengers being taken away on stretchers and fire-fighters using ladders to search for those trapped in wreckage.
Many others appeared to have minor injuries.
Former Congressman Patrick Murphy 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,” Patrick Murphy 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.
Paul Cheung said he saw “some people mangled up”.
He said just before the crash the train “started to decelerate, like someone had slammed the brake”.
Paul 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.
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