Preliminary investigation of the in vitro and in vivo efficacies of different extracts from the leaves of Vernonia amygdalina (VA), a plant widely used in Nigeria was evaluated in Balb/C mice infected with a laboratory strain of Leishmania major (L. major). The ability of the methanol, hexane and aqueous extracts of the plant to suppress the infection rate and its cytotoxicity on macrophages and L929 cells were determined in the in vitro study. The in vivo study evaluated time course of infection, lesion progression and the histopathology of cutaneous lesions, liver and spleen after inoculation with metacyclic promastigotes. Methanolic extract of VA containing high levels of flavanoids, was the most potent extract as it showed the highest suppression on infectivity and viability of intracellular amastigotes at a concentration lower than that which elicited cytotoxicity on macrophages. Treatment of infected mice with methanolic extract of VA showed delayed onset of disease with a significant reduction in lesion size and attenuation of the histopathological outcome characterised by intact epidermis and less tissue destruction in skin, spleen and liver. In conclusion, these results demonstrate that VA has potent antileishmanial properties which warrants further investigation into the immunological mechanism.