Non-steroidal anti-inflammatory drugs (NSAIDs) exhibit several divergent biological effects. In this study, we investigated the effect of indomethacin on melanin synthesis using B16F1 melanoma cells. Indomethacin inhibited α-melanocyte stimulating hormone (α-MSH)-enhanced melanin synthesis in a dose-dependent manner. Western blotting analysis revealed that indomethacin significantly suppressed tyrosinase and Mitf protein levels. In a luciferase reporter assay, we found that indomethacin reduced tyrosinase promoter activity. Moreover, real-time RT-PCR analysis showed that indomethacin lowered mRNA levels of melanogenic genes, including Mitf. Together, our findings indicate that indomethacin inhibits melanogenesis via the suppression of Mitf transcription.