The train had left Bengaluru at 0615 hrs and derailed at 0735 hrs between Anekal Road and Hosur on Bangalore City-Salem Section, about 45 km from Bengaluru, Railways said.
Railway Minister Suresh Prabhu said a boulder fell on the track and the train hit it.
"I am personally monitoring it and in touch with State and local administration," he tweeted.
Prabhu said he has directed all senior officers to rush to the spot with help. Law Minister Sadanand Gowda has reached the accident site, near the border of Karnataka and Tamil Nadu.
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"Five deaths (confirmed) so far," Bangalore Divisional Railway Manager Anil Kumar Agarwal, who rushed to the accident site, told PTI.
"At least five to six persons have died. Exact number of casualties would be known after some time as rescue and relief operations are still underway," Karnataka Home Minister K J George told reporters here.
Prabhu said an inquiry had been ordered to fix responsibility and for corrective action to prevent such unfortunate accidents. He said he was monitoring "action" regularly.