Introduction: Elephantiasis is a medical condition associated with skin thickening and excessive swelling of the lower limbs. It is caused by parasitic nematodes which are filarial in nature; hence, it is also known as lymphatic filariasis. The condition is classified into filarial and nonfilarial elephantiasis. Filarial elephantiasis is caused by infection with nematode worms which are transmitted by several genera of mosquitoes. Nonfilarial elephantiasis is a result of cases such as tuberculosis, sexually transmitted infections, leprosy, and repeated streptococcal infections, leading to elephantiasis. South African population is at risk of the disease and treating it is still a problem. This study documents medicinal plants that are used for the treatment of elephantiasis and related infections in the OR Tambo District municipality, Eastern Cape Province, South Africa. Materials and Methods: An ethno botanical survey of medicinal plants used against elephantiasis in King Sabata Dalindyebo, Ingquza-Hill and Nyandeni municipal areas in the OR Tambo District of the Eastern Cape Province was conducted using structured questionnaires. The information was gathered from 30 traditional healers, 4 herbalists, and 3 young people with indigenous knowledge. Results and Discussion: A total of 29 plant species belonging to 23 families that are used to treat elephantiasis were recorded. Convolvulaceae (Ipomoea oblongata), Dioscoreaceae (Dioscorea sylvatica), Gunneraceae (Gunnera perpensa), Hypoxidaceae (Hypoxis hemerocallidea), and Ranunculaceae (Clematis brachiata) were the most frequently mentioned in all three municipal areas. The H. hemerocallidea had the highest use-value (0.31), followed by Elephantorrhiza elephantina (0.27) and G. perpensa (0.24). Bark, root, rhizome and leaf decoction and infusion, as well as cooked bark or leaves are commonly used to treat elephantiasis. Some plant parts are ground into powder, mixed with water and applied on affected skin as poultice.