The engine and nine coaches of Rawalpindi-bound Jaffar Express derailed from track this morning at Ab-i-gum area in Bolan district of the province, officials said.
The train was coming from provincial capital Quetta.
The driver of the train and his assistant are among those killed in the accident.
Balochistan Home Minister Sarfaraz Bugti said at least 16 people were killed and more than 150 others injured.
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"The death toll may rise as some of the injured were in critical conditions," Railway Minister Saad Rafique said.
TV footage shows the derailed coaches and passengers luggage scattered at the place of accident.
Pakistan Railways launched an investigation.
According to the initial investigations, the accident occurred due to over speeding which caused failure of brakes.
Bugti said military was helping in rescue operation. He said 26 injured were shifted to hospitals with the help of two army helicopters.
On November 1, four persons were killed and six others injured when a remote-controlled bomb placed close to railway track struck the Jaffar Express on the outskirts of Quetta.
Those killed were railway employees. The outlawed United Baloch Army had claimed responsibility for the blast.
Trains are often targeted by Baloch militants fighting for greater control over the mineral resources of the province.