Tyrosinase is a key enzyme responsible for melanin biosynthesis and is effective in protecting skin damage caused by ultraviolet radiation. As part of ongoing efforts to discover potent tyrosinase inhibitors, we systematically designed and synthesized thirteen ()-benzylidene-1-indanone derivatives (-) and determined their inhibitory activities against tyrosinase. Among the compounds evaluated, was the most potent inhibitor of mushroom tyrosinase (IC = 0.034 µM, monophenolase activity; IC = 1.39 µM, diphenolase activity). Kinetic studies revealed that demonstrated a mixed type of tyrosinase inhibition with value of 2.4 µM using l-DOPA as a substrate. molecular docking simulations demonstrated that can bind to the catalytic and allosteric sites of tyrosinase to inhibit enzyme activity which confirmed experimental studies between and tyrosinase. Furthermore, melanin contents decreased and cellular tyrosinase activity was inhibited after treatment. These observations revealed that is a potent tyrosinase inhibitor and potentially could be used as a whitening agent for the treatment of pigmentation-related disorders.