The accident occurred in the Limpopo province during the night towards Monday when the bus was driving through "a hilly part" of a highway.
It is unclear how many people were in the bus and what caused the accident. In addition to the 42 dead, there are 49 injured.
The deceased are citizens of Zimbabwe and Malawi and the President of South Africa calls the accident a tragedy and expresses his sympathies to "our sister countries".
An investigation has been opened to clarify what happened.
