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[Display omitted] • Leishmaniasis that affects nearly 0.7–1.3 million people annually, has so far limited and high toxic therapeutic options. • Novel coumarin-isatin hybrids have been synthesized and characterized. • Docking study reveals Spf-6 , Spf-8 and Spf-10 as the best lead molecules. • All the compounds were evaluated for their leishmanicidal potential. • Three compounds were highly active against L. tropica promastigotes and amastigotes. Leishmaniasis being one of the six major tropical diseases that affects nearly 0.7–1.3 million people annually, has so far limited and high toxic therapeutic options. Herein, we report the synthesis, in silico, and in vitro evaluations of novel coumarin-incorporated isatin hydrazones (Spf-1 – Spf-10) as highly potent and safe antileishmanial agents. Molecular docking was initially carried out to decipher the binding confirmation of lead molecules towards the active cavity of the target protein (Leishmanolysin gp63) of Leishmania tropica. Among all the docked compounds, only Spf-6 , Spf-8, and Spf-10 showed high binding affinities due to a pattern of strong conventional hydrogen bonds and hydrophobic π-interactions. The molecular dynamics simulations showed the stable pattern of such bonding and structure-based confirmation with a time scale of 50 ns towards the top compound (Spf-10) and protein. These analyses affirmed the high stability of the system. Three out of ten compounds evaluated for their antileishmanial activity against Leishmania tropica promastigotes and amastigotes were found to be active at micromolar concentrations (IC 50 range 0.1–4.13 μmol/L), and most importantly, they were also found to be highly biocompatible when screened for their toxicity in human erythrocytes. [ABSTRACT FROM AUTHOR]