More than 12 carriages of the overnight train, travelling between Karachi and Lahore, came off the rails near the city of Mehrabpur in Sindh province, leaving some of the carriages submerged under water.
The express train was packed with passengers returning home for the Islamic festival of Eid al-Adha.
Rescue workers struggled with the large numbers of casualties - including children - in the dark and cold and did not have equipment to cut open the carriages. Many local people turned out to help, carrying the injured away on rickshaws, motor-scooters and donkey carts.
Officials said the likely cause of the crash was a faulty track.
Pakistan has a history of deadly accidents on its ageing railway system. More than 130 people were killed when three trains collided in Sindh province in July 2005 in the country's worst train disaster for 15 years.
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