Dioscorea dregeana is commonly sold on the 'muthi ' markets in South Africa. It may be used in different ways for different purposes. The Zulus use it as a sedative in the treatment of epilepsy, hysteria, insomnia and acute psychosis. The Zulu word 'isidikwa ' means 'drunkard', referring to the reported effects that it may have. It is also used topically for scabies. In ancient times, it was used as a general anaesthetic to enable fractures of the limb to be manipulated and stabilised by traditional bone-setters. The fresh tuber is generally taken orally as a weak decoction, with an adequate dose resulting in sleep within 20-30 minutes. Dioscorea dregeana is sometimes combined with Boophone disticha for the purpose of divination.

However, human deaths have been reported after the use of the plant as famine food or as medicine. This species is reported to make a person 'mad drunk', and it has been used in poison bait to destroy monkeys. This Dioscorea, due to its toxicity, is often planted to eradicate moles (intukuzi ) in the fields and home gardens. It is often planted together with crops, especially root and tuber plants, such as amabhatata (Ipomoea batatas, sweet potato) and amadumbe (Colocasia esculenta, coco yam).