The aim of the present study was to investigate the potential inhibitory effects of nodakenin, a coumarin glucoside derivative from the root extract of Angelica gigas Nakai (AGN), on melanogenesis and its underlying mechanisms in B16F10 melanoma cells. The inhibitory effects of nodakenin on melanogenesis were evaluated by determining melanin contents and tyrosinase activity in α -melanocyte stimulating hormone (α-MSH)-treated B16F10 melanoma cells. The mechanisms associated with the anti-pigmentation effect of nodakenin were investigated by quantitative real-time PCR and immunoblotting analysis. Using the UVB-irradiated conditioned media culture system and UVB-irradiated co-cultivation system of HaCaT keratinocytes and B16F10 melanoma cells mimicking in vivo melanin biosynthesis, the effect of nodakenin on melanin production was evaluated. Melanin content analysis showed that nodakenin decreased cellular melanin biosynthesis in α-MSH-treated B16F10 cells. Immunoblotting revealed that CREB phosphorylation, MITF, a mastering transcription factor of melanogenesis and its downstream genes tyrosinase, tyrosinase-related protein 1, and tyrosinase-related protein 2 were downregulated by nodakenin in a dose-dependent manner. Interestingly, nodakenin did not affect the phosphorylation of PKA and p38 MAPK but the phosphorylation of ERK1/2 and MSK1. In addition, the inhibition of melanin accumulation by nodakenin in the UVB-irradiated conditioned media culture system and UVB-irradiated co-cultivation system of HaCaT and B16F10 cells suggests that nodakenin has potential as an anti-pigmentation activity. These data suggest that nodakenin inhibits the melanogenesis in B16F10 cells by interfering the ERK/ MSK1/CREB axis and thus preventing MITF expression.