We synthesized (Z)-5-(2,4-dihydroxybenzylidene)thiazolidine-2,4-dione (MHY498) as a potential tyrosinase inhibitor. MHY498 potently inhibited mushroom tyrosinase activity (mean IC50 = 3.55 μM) in a dose-dependent manner. MHY498 was more potent than the well-known tyrosinase inhibitor, kojic acid (mean IC50 = 22.79 μM). When tested in B16F10 melanoma cells treated with α-melanocyte stimulating hormone (α-MSH), MHY498 inhibited murine tyrosinase activity and decreased melanin production without inducing cytotoxicity. Docking models showed that the binding affinity of MHY498 to tyrosinase was higher than that of kojic acid, and docking simulation results indicated that the tyrosinase binding moieties of MHY498 and kojic acid were similar. Western blotting showed that tyrosinase inhibition by MHY498 partly resulted from the expressional modulations of tyrosinase and its transcription factor, microphthalmia-associated transcription factor, via the cAMP-PKA-CREB pathway. These findings suggest that MHY498 could be useful as an antimelanogenic agent for the prevention and treatment of diseases associated with skin pigmentation.