The bus was headed to Karachi from Khyber-Pakhtunkhwa province in the north-west when it collided with the truck near Theri bypass in Sukkur district of Sindh. The bus quickly caught fire after its fuel tank exploded.
At least 60 people were killed in the accident, Afzal Somoro, a police official, told PTI.
An initial probe shows that the bus driver's carelessness caused the accident, police said, adding the bus was carrying about 70 passengers and was clearly overloaded.
"They were so many casualties because after the collision the fuel tank of the bus exploded," Khawaja said.
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However, most of those killed didn't die from burn related injuries, said Jam Mehtab, Sindh Health Minister.
"The casualties occurred on impact and those killed include 21 women and 19 children, all below the age of 14," Mehtab said, adding that several others were injured in the accident.
Medical Superintendent of Khairpur Civil Hospital Jaffar Soomro said, that the death toll is likely to rise.
Prime Minister, Nawaz Sharif has also expressed his condolences over the accident and ordered an enquiry.
In April, a bus collided with a tractor-trailer in Sindh, killing 42 people, while in March another crash between two buses and a petrol tanker left 35 dead.