The tornado touched down near the city of New Hanover, according to authorities.
"Two adults were unfortunately declared dead on the scene," paramedic Ross Campbell, from the medical response company ER24, told ABC News. "ER24 treated and transported nine patients for minor to moderate injuries to various hospitals in the area. Provincial medics treated and transported 11 others, bringing the total number of injuries on the scene to 20."
"An adult woman who had suffered serious injuries as a result of losing control of her vehicle during the storm was treated with Advanced Life Support interventions before being taken to Mediclinic Pietermaritzburg for further care," he added.
Campbell said many animals were reported to have been injured or killed in the area and power lines are also down.
"There is an extreme danger to life due to fast flowing rivers," the weather service said in a statement. "There is also a possibility of landslides and soil erosion along highly elevated areas which might lead to further disruption to traffic flow. Accumulated rainfall amounts for Thursday and Friday could exceed 100-150 mm [about 4 to 6 inches] in places over KwaZulu-Natal."
Tornadoes are not a regular occurrence in South Africa and the weather service said the strength of Tuesday night's twister has yet to be determined.