The bus carrying 73 passengers crashed into an oncoming truck on a main road near the town of Chibombo, north of Lusaka.
"I can confirm that 53 people have died in the accident," Harry Kalaba, an official in the vice president's office, said at the crash site.
The cause of the crash is being investigated but witness accounts suggest the crash happened as the bus was trying to swerve to avoid another oncoming vehicle.
Zambian roads are extremely dangerous, most roads are narrow and buses and other vehicles are often overloaded or poorly maintained.
"Of course we know the best solution is widening the road but for now we just have to appeal to the drivers to be cautious and ensure they behave responsibly," Steven Kapyongo, Home Affairs Deputy Minister said.
Survivors suffering from cuts and bruises were being treated in a nearby hospital.
"I can't even feel these bruises, it is just my shoulder because I think that's what got hit in the back the most," one survivor said.
Others, with more serious injuries were taken to Lusaka.
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