Cathepsins have emerged as potential drug targets for melanoma therapy and engrossed attention of researchers for development and evaluation of cysteine cathepsin inhibitors as cancer therapeutics. In this direction, we have designed, synthesized, and assayed in vitro a small library of 30 low molecular weight functionalized analogs of chalcone hydrazones for evaluating structure-activity relationship aspects and inhibitory potency against cathepsin B and H. The maximum inhibitory effect was exerted by chalcone hydrazones, which are open chain analogues followed by their cyclized derivatives, pyrazolines and pyrazoles. All the synthesized compounds were established as reversible inhibitors of these enzymes. Cathepsin B was selectively inhibited by the compounds in each series. Compounds 1d, 2d and 4d were recognized as most potent inhibitors of cathepsin B in this study with Ki values of 0.042 μM, 0.053 μM and 0.131 μM whereas 1b (Ki=1.111 μM), 2b (Ki=1.174 μM) and 4b (Ki=1.562 μM) inhibited cathepsin H activity effectively. And, preeminent cathepsin B inhibitors were -NO2 functionalized however, -Cl substituted moieties were the most persuasive inhibitors for cathepsin H among all the designed compounds. Molecular docking studies performed using iGemdock provided valuable insights.