Visceral leishmaniasis, the most severe form, affects thousands of people annually. Current drugs in practice fail to provide an absolute cure. Globally, treatment relies on a single dose of liposomal amphotericin B, which requires a costly setup and cold chain to maintain. Natural molecules remain the vital sources of therapeutic ingredients in modern medicine. Meripilus giganteus is traditionally consumed by the people of the North-eastern regions of the Himalayas, India. In this study, we planned for the stepwise bioactivity-guided isolation of natural molecules from M. giganteus and to synthesize more potential therapeutic derivatives against the drug-resistant Leishmania infection. HPLC chromatogram of ethyl acetate extract obtained from M. giganteus revealed the presence of ethyl linoleate as the most active anti-leishmanial molecule. Several derivatives of ethyl linoleate were synthesized and evaluated against Leishmania promastigotes. Among them, a single epoxygenated variant of ethyl linoleate, ethyl (Z)-8-(3-(oct-2-en-1-yl) oxiran-2-yl) octanoate (EL3), showed promising anti-leishmanial activity against both drug-sensitive and drug-resistant Leishmania donovani . The lead derivative disrupts the biosynthesis of trypanothione from glutathione and spermidine, making the parasite vulnerable to the oxidative burst inside the host. Interestingly, the lead derivative was found to be more efficient against the drug-resistant L. donovani , in vivo . Besides this, it has almost no toxicity towards host cells. Considering the urgency for new drug development, we propose this novel semi-synthetic derivative as a potent therapeutic lead.