Indole and its derivatives, heterocyclic compounds with broad therapeutic potential, have seen limited study in melanogenesis. Here, our virtual screening identified 15 indole derivatives that potentially interacted with tyrosinase (TYR), a key enzyme in melanogenesis. Nine of the 15 indole derivatives tested significantly decreased tyrosinase activity, and 3-hydroxy-5-bromo-(3-indolyl)-2‑carbonyl indole (designated as YM818) exhibited highest inhibitory rate at 74.28 % with IC50 of 0.372 mmol/L. Surface plasmon resonance and fluorescence quenching assays demonstrated the direct interaction between YM818 and TYR with KD value 94.84 ± 45.27 μmol/L. YM818 treatment reduced cellular melanin content to 35.8 %. Furthermore, YM818 treatment enhanced AKT protein phosphorylation, leading to the downregulation of melanogenesis-related proteins, including MITF, TYR and TRP1. In vivo zebrafish studies confirmed the inhibitory effects of YM818 on melanogenesis. Additionally, YM818 disrupted melanin transfer by suppressing the expression of protease-activated receptor-2 (PAR-2) gene, a G protein-coupled receptor that plays a crucial role in mediating cellular responses to serine proteases, including keratinocyte phagocytosis and melanin transfer. YM818 also exhibited robust antioxidant activity, with 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical scavenging IC50 values comparable to vitamin C and significantly reducing intracellular ROS levels in a dose-dependent manner. Taken together, these findings highlight YM818 as a promising anti-melanogenic agent, offering valuable insights into the development of novel anti-melanin drugs and tyrosinase inhibitors.