Cell death pathways related to ferroptosis are implicated in the progression of melanoma. Emerging data reporting the upregulation of microRNA (miR)-130b-3p in melanoma indicate the potential implication of miR-130b-3p in this malignancy. Herein, we aimed to identify whether and how miR-130b-3p regulated ferroptosis in melanoma cells. Melanoma cells (A375, G-361) were treated with erastin or RSL3 to mimic ferroptosis in vitro. Viability, lipid peroxidation level and ferrous ion content in melanoma cells were then assessed in response to manipulation of miR-130b-3p expression. Luciferase assay was conducted to determine the binding of miR-130b-3p to Dickkopf1 (DKK1). Western blot assay was conducted to determine the expression of molecules related to nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. The results indicated that miR-130b-3p exerted an inhibitory role in erastin or RSL3-induced ferroptosis, evidenced by reductions in lipid peroxidation and ferrous ion content. By suppressing the expression of target gene DKK1, miR-130b-3p activated the Nrf2/HO-1 pathway, whereby repressing ferroptosis. miR-130b-3p blocked the antitumor activity of erastin. Further, in vitro findings were reproduced in an in vivo murine model. Together, these data suggest the potential of miR-130b-3p to inhibit ferroptosis in melanoma cells and the mechanism was related to DKK1-mediated Nrf2/HO-1 pathway.