Department spokesperson Moeti Mmusi said the accident, which involved two taxis, took place at approximately 1:00 on the N17 between Leandra and Kinross.
Two women and two men – aged in their late 30s – were killed in the crash while eleven people sustained serious injuries.
All the deceased and 10 of the injured people were the occupants of one taxi. The other vehicle only had one occupant.
“At this point, the cause of the collision remains unclear. However, a probe is already underway,” said Mmusi.
The spokesperson said the taxi with the single occupant had been travelling from Kinross towards Leandra. “The injured were rushed to nearby hospitals.”
Mpumalanga DCSSL MEC Vusi Shongwe called for motorists to be vigilant on the road over the Easter weekend.
In unrelated incidents, two people were killed in motor vehicle accidents in Limpopo shortly before midnight on Thursday.