Tapinanthus dodoneifolius (Loranthaceae), has diverse ethnomedicinal uses which include the management of mental illness, epilepsy, diarrhoea, malaria, pain and hypertension. Despite these uses and many validated pharmacological properties, the safety of T. dodoneifolius is yet to be evaluated. This study therefore, aimed to evaluate the sub-acute toxicity profile of methanol whole plant extract of T. dodoneifolius in rats. Phytochemical screening of the plant extract was carried out according to standard protocols. Oral median lethal dose (LD50) was estimated using the Organisation for Economic Cooperation and Development (OECD) 423 limit test. Doses of 250, 500 and 1000 mg/kg of the extract were administered for 28 consecutive days using the OECD 407 guideline. The body weights of animals were taken at 7 days interval within 28 days period. Thereafter, animals were sacrificed and blood samples collected for haematological, biochemical and electrolyte analysis. The spleen, heart, liver, kidney, lungs and stomach were also collected for histological examinations. The extract contains alkaloids, cardiac glycosides, saponins, tannins, flavonoids, steroids, terpenoids and carbohydrate. The LD50 was found to be ≥ 5000 mg/kg. The extract showed significant (p≤0.05) increase in body weight and decrease in alkaline phosphatase (ALP). There was no significant difference in the mean organ weight. The histological studies did not reveal any serious abnormalities in the organs examined. The methanol whole plant extract of T. dodoneifolius does not possess the toxic effects that could affect its ethnomedicinal uses.