The study was intended at evaluating the anti-proliferating effect of mushrooms used in traditional folklore of Santal tribal population in India against Leishmania donovani (MHOM/IN/83/AG83). A total of eighteen extracts, three estracts from each mushroom [(80% ethanol extracted; Fa), (water-soluble polysaccharide fraction; Fb), (polyphenolic fraction; Fc)], from six wild mushrooms were obtained. These extracts were tested against the promastigotes and amastigotes for their antileishmanial capacity. Fa fractions (250 μg/mL) of Astraeus hygrometricus and Tricholoma giganteum significantly inhibited the growth of L. donovani promastigotes and interfered in lipid biosynthesis. Moreover, both fractions induced apoptosis in promastigotes. Water soluble Fb fractions of A. hygrometricus, Russula laurocerasi, Russula albonigra, Termitomyces eurhizus, Russula delica and polyphenolic Fc fraction of R. laurocerasi were found to inhibit the replication of intracellular amastigotes in macrophages dose dependently. Significantly, 50% inhibitory concentration of the active extracts against intracellular amastigotes induced release of nitric oxide and IL-12 in murine macrophages and dendritic cells assay and also found considerably non-toxic on murine splenocytes. Results of this study can be used as a basis for further phytochemical and pharmacological investigations in the effort for search of novel anti-leishmanial leads.