The male driver of the train and an as-yet-unidentified person died when the train left the tracks at Wallan near the Hume Freeway just before 8pm, about 45 kilometres north of Melbourne.

The train had stopped earlier that day at Wagga and Junee.

A Victoria Police statement said the train derailment was being investigated.

"The male driver and another person, who is yet to be formally identified, died at the scene," the statement said.

"Twelve others were transported to hospital with non-life-threatening injuries. A report for the Coroner will be prepared.

"Police will investigate the cause of the incident in conjunction with National Rail Safety Regulator, Australian Transport Safety Bureau, and Work Safe.

"Police are appealing for anyone who was on board the train and did not make contact with emergency services or who had a booking but did not travel to contact Crime Stoppers on 1800 333 000."

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The train had left Sydney Central Station at 7.40am on Thursday and had been due at Melbourne's Sourthern Cross station at 6.30pm.

The service was carrying 153 passengers and running two hours behind schedule at the time of the crash.

Riverina MP and federal Transport MInister Michael McCormack released a joint statement on Thursday night along with Victorian Transport Minister Melissa Horne and NSW Transport Minister Paul Toole.

"The federal, NSW and Victorian governments are working closely to support all those involved in the incident," the statement said.

"A range of support measures will be available to passengers, crew and their families.

"The Australian Transport Safety Bureau and the Office of the National Rail Safety Regulator will conduct a full and thorough investigation to establish the cause of the incident.

"Our thoughts and prayers are with all those involved in the incident."