Nepeta (Lamiaceae) is an important genus with beneficial medicinal properties. N. sintenisii Bornm. has been used in folk medicine of Iran to cure various diseases. We investigated the anti-melanogenesis effects of n -hexane, MeOH, CH 2 Cl 2 , n -BuOH, EtOAc, and H 2 O extracts isolated from the plant in B16 melanoma cells. Various assays including cytotoxicity, mushroom tyrosinase inhibition, inhibition of cellular tyrosinase, melanin content, the amount of reactive oxygen species and western blotting were done to assess the plant activities on melanogenesis inhibition. All extracts of N. sintenisii could significantly reduce both tyrosinase activity and the cellular melanin content. Reactive oxygen species were also significantly decreased following the treatment of cell with n -BuOH and EtOAc extracts with no cytotoxicity. The plant significantly decreased the amount of microphthalmia-associated transcription factor proteins. Collectively, N. sintenisii inhibited melanin synthesis and tyrosinase activity in B16 melanoma cells with no cytotoxic effects. Hence, it might merit further investigations for elucidation of anti-hyperpigmentation agents.