The passenger express was going from Karachi to Lahore when about 12 of its 16 carriages came off the rails near Mehrabpur, about 250 miles north of Karachi, the officials said.
Rescue workers recovered 50 bodies from the wreckage and were calling in cutting equipment to gain access to more of the carriages, said Sikander Ali, a senior police official at the scene.
Other officials said dozens more passengers were injured and that relief trains were being sent to provide help.
The train, which derailed at about 2 a.m., was loaded with passengers traveling home for the Islamic holiday of Eid ul-Adha. The cause of the crash was not immediately clear.
Deadly accidents are a regular occurrence on Pakistan's sprawling, colonial-era railway network.
A speeding train struck a crowded bus at a railway crossing near Lahore in October, killing 12 people and injuring about 50 others. About 133 people died in July 2005 when three trains collided in southern Pakistan.