Several carriages of the Hazara Express overturned near Sahara railway station in Nawabshah, about 275 kilometres 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.
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.
A railways spokesperson in Karachi said at least eight carriages went off the track.
Some people were still trapped inside a train carriage, according to local broadcaster Geo.
"We don't know what happened, we were just sitting inside," said one dazed woman who was rescued from a carriage, while others were being taken away by ambulance.
An emergency has been declared in the main hospitals in Nawabshah and neighbouring districts of Sindh.
Videos posted on social media show dozens of people at the site of the accident, with some passengers climbing out of the overturned carriages.
Train services to the interior districts of Sindh have been suspended.
Sindh Information Minister Sharjeel Memon told BBC News that the government's top priority was "the rescue work, which we are totally focused on".
In 2021, two trains travelling in Sindh province collided, killing at least 40 people and injuring dozens.
Between 2013 and 2019, 150 people died in such incidents, according to local media reports.