Melanogenesis is a process of melanin synthesize, which is a primary response for the pigmentation of human skin. Tyrosinase is a key enzyme, which catalyzes a rate-limiting step of the melanin formation, natural products have shown potent inhibitors, but some of these possess toxicity. Numerous synthetic inhibitors have been developed in recent years may lead to the potent anti-tyrosinase agents. Therefore its inhibition may be an efficient way for the development of depigmenting agents. A novel series of 2-arylidine-1H-indene-1,3(2H)-dione analogs were designed, synthesized and screened for their in vitro tyrosinase inhibitory activity. 3d derivative bearing nitrothiophene revealed excellent anti-tyrosinase activity with an IC50 value of 3.55 μM comparable to kojic acid as a positive control. 3d as the most potent inhibitor and 3f as the least active derivative were subjected to in silico evaluations considering the 3D conformations, ΔGb of bindings and interactions within the active site of tyrosinase.