Visceral leishmaniasis (VL) is one of the most devastating diseases of the tropical region caused by protozoan parasite Leishmania donovani. So far, there is no effective drug and vaccine available against this fatal disease. The DEAD-box RNA helicase is quite essential for the RNA processing, amastigote differentiation and infectivity in Leishmania. In this study, L. donovani DEAD-box RNA helicase (LdHel-67) was evaluated as a potential drug target against VL. Using in-silico approach we have identified ligands that can specifically bind to this protein by using various application of Schrodinger (Maestro, version 10.5, LLC, NY 2016-1). We have shortlisted 10 ligands with positive interaction against the selected target based on their in-silico activity and identified three potential compounds viz. carvacrol, vanillin, and the p-coumaric acid having a maximum affinity for this LdHel-67 protein. After vigorous in-silico analysis, these ligands were tested in-vitro against L. donovani. These ligands were safer on the J774A.1 macrophages and were effective against promastigotes and disease-causing intracellular amastigotes. This is the first report of antileishmanial potential of carvacrol, vanillin and p-coumaric acid targeting LdHel-67. Thus, the present study will help in the search for target specific inhibitors to facilitate the development of new drugs against VL.