Several others were also injured, some with severe burns, in the accident on Thursday night, police said.
At least 42 passengers have been confirmed dead, Zimbabwe police said on Friday, after a suspected gas tank exploded on a bus, with pictures showing the burned-out wreckage of the vehicle.
"At the moment we know that more than 42 people died," police spokeswoman Charity Charamba told AFP after the accident late on Thursday, with state media reporting a gas tank belonging to a passenger was believed to have exploded.
"Our police officers are at the scene," Charamba added.
The state-owned Herald newspaper said on its Twitter feed that "it is suspected a gas tank belonging to one of the passengers caused the inferno in the bus.
"Dozens have been confirmed dead and several others injured through burns."
Photos posted on Twitter by the Zimbabwe Red Cross show the remains of a bus that was completely incinerated.
Zim Red Cross first aid teams responded to a horrific accident around midnight at the 56km peg from Gwanda towards Beitbridge involving a South African bound bus. A total of 24 people have been ferried to Hospital while the number of deaths is still to be confirmed. pic.twitter.com/GSu3xRHFB7— Zimbabwe Red Cross (@ZrcsRed) November 16, 2018
The accident happened in Gwanda district, about 550 km south of Harare, Zimbabwe's capital.
Last week, 47 people were killed when two buses collided on a road between the capital Harare and the eastern town of Rusape.
President Emmerson Mnangagwa said road safety had to be improved after that crash.
Traffic accidents are common in Zimbabwe, where roads are riddled with potholes due to years of underfunding and neglect, and driving standards can be poor.
In June last year, 43 people were killed in a bus crash in the north, along the highway leading to neighbouring Zambia.