AbstractMelanogenesis is a process to synthesize melanin, which is a primary responsibility for the pigmentation of human skin, eye and hair. In order to study the effect of polyoxometalates on tyrosinase activity and melanin content in mouse melanocytes, four polyoxometalates with Dawson structure were synthesized. Intracellular and docking studies have shown that the two transition metal phosphomolybdic acids (H8[P2Mo17Fe(OH2)61] and H8[P2Mo17Ni(OH2)61]) are highly effective melanogenesis inhibitors with 22.4 % and 24.1 % inhibitory activities at a concentration of 200 μM. Among the four POMs synthesized, the three phosphomolybdic acids showed extremely significant inhibitory effects on the tyrosinase activity in B16 cells (p<0.0001), and the inhibitory activities were 77.5 %, 79.3 % and 44.4 % at a concentration of 200 Μm, respectively. MTT reduction experiments show that the three polyacids (H6[P2Mo18O62], H8[P2Mo17Co(OH2)61] and H8[P2Mo17Ni(OH2)61]) have basically no effect on the viability of B16 cells. Molecular dynamics simulation studies also show that H8[P2Mo17Ni(OH2)61] forms a stable complex with tyrosinase, with a docking fraction of −51.54 kcal/mol. Based on intracellular and docking studies, we believe that H8[P2Mo17Ni(OH2)61] is a promising candidate for safe cosmetic development.