Several carriages of the Hazara Express overturned near Sahara railway station in Nawabshah, about 275km (171 miles) from the largest city Karachi.
Wounded passengers were moved to nearby hospitals. Rescue teams are trying to free people from the twisted wreckage.
Accidents on Pakistan’s antiquated railway system are not uncommon.
Videos posted on social media showed dozens of people at the site of the accident, with some passengers climbing out of the overturned carriages.
Railway Minister Saad Rafiq said initial investigations showed the train was travelling at normal speed and they were trying to establish what led to the derailment. It could be the result of a mechanical fault or sabotage, he added.
Authorities have dismissed reports the track was flooded.
A railways spokesperson in Karachi said at least eight carriages went off the track.
He said military and paramilitary troops along with rescue workers were on the scene and helped to rescue passengers trapped inside the train carriages.
The most seriously injured passengers were transported to distant, better-equipped hospitals in military helicopters.
Officials said rescue operations were completed in the early evening on Sunday.