Melanoma-associated death is mainly caused by metastatic disease whereby increased melanin levels correlate with decreased melanoma patient survival. Which role melanin plays in melanoma-associated death is unknown. Here, we show that melanin protects circulating melanoma cells from ferroptosis, enhancing their metastatic potential. Melanin levels in patient-derived uveal melanoma cells as well as cutaneous and conjunctival melanoma cell lines correlate with their metastatic potential in zebrafish xenografts. Furthermore, increasing or decreasing intracellular melanin levels in melanoma cells is sufficient to enhance or reduce their metastatic potential, respectively. In addition, the expression of genes encoding melanosomal enzyme TYRP1 and also the ferroptosis-related proteins GPX4 and VDAC1 is strongly associated with reduced melanoma-specific survival. Moreover, melanin depletion increased ferroptosis sensitivity leading to an enhanced efficacy of ferroptosis induction. Collectively, our results reveal that combined inhibition of melanin biosynthetic enzymes and induction of ferroptosis has potential as a treatment strategy of metastatic melanoma.