Visceral leishmaniasis (VL) is the deadliest form of leishmaniasis without a safer treatment option. This study implies drug repurposing to find a novel antileishmanial compound, namely febrifugine dihydrochloride (FFG) targeting Leishmania antioxidant system. Starting with virtual screening revealed the high binding affinity and lead likeness of FFG against the trypanothione reductase (TR) enzyme of Leishmania donovani, followed by experimental validation. The promastigotes inhibition assay gave the IC50 concentration of FFG and Miltefosine (positive control) as 7.16 ± 1.39 nM and 11.41 ± 0.29 μM, respectively. Their CC 50 was found as 451 ± 12.73 nM and 135.9 ± 5.94 μM, respectively. FFG has been shown to increase the reactive oxygen species (ROS), leading to apoptosis-like cell death among L. donovani promastigotes. Spleen touch biopsy resulted in 62% and 55% decreased parasite load with FFG and miltefosine treatment, respectively. Cytokine profiling has shown an increased proinflammatory cytokine response post-FFG treatment. Moreover, FFG is safe on the liver toxicity parameter in mice post-treatment. [Display omitted] • Drug repurposing approach was applied to identify new application of febrifugine dihydrochloride (FFG) against visceral leishmaniasis. • Febrifugine dihydrochloride inhibited the trypanothione reductase of Leishmania donovani. • Febrifugine dihydrochloride induces the pathogen specific apoptosis to kill Leishmania donovani. • Febrifugine dihydrochloride has shown oral efficacy against the Leishmania donovani infected animal model. [ABSTRACT FROM AUTHOR]