Gnidia species contains high levels of toxic diterpene esters and coumarins. However, their roots are used medicinally for various types of ailments, such as constipation, boils, burns, snakebites, coughs, insanity and poor appetite. The roots of G. polycephala are used for several ailments in Botswana. The leaves of G. capitata and G. gymnostachy are ground to a snuff, smoked or used as a poultice to treat stomach-ache, earache or toothache.

In some parts of Africa, the crushed rhizome of Gnidia kraussiana, mixed with Strophanthus hispidus, is used as an effective arrow poison. In Malawi, Zimbabwe, and further north, the plant is utilised as a fish poison. In South Africa, though the plant is well known for its extreme toxicity, its decoctions are used to ease trauma in childbirth. The root of umarhedeni (as the plant is known in Xhosa) is also very effective for the treatment of sexually transmitted infections, known as ukubhajwa. The correct procedure for preparation of this medicine must be strictly adhered to: the boiling decoction of the root must be cooled and reheated ten times before the medicine is ready for use. A cup of the medicine must be filled to the level of the first joint of the index finger (an overdose could be fatal) and is administered as an enema.

In livestock, Gnidia species poisoning result in severe diarrhoea, weakness, fever and a rapidly weakening pulse or even death if large quantities are ingested. In humans, powdered material of Gnidia species causes irritation of the nose and throat, followed by coughing and sneezing, and eventually headache and nausea.