Ion channels are pore-forming membrane proteins known to be involved in all hallmarks of cancer. Due to their expression on the cell surface, ion channels constitute a group of potential therapeutic targets offering high accessibility. NMDA (N-methyl-D-aspartate) receptors are a subtype of ion channels that exhibit unique features including high calcium permeability, and binding of glutamate along with a co-agonist to their binding domains in order to activate. Here we show that a NMDA type ion channel, GluN2C is critically required for survival of human melanoma cells. Publicly available microarray datasets from Gene Expression Omnibus (GEO) were used in order to identify the differentially expressed ion channel genes in 127 melanoma patient samples relative to benign nevi and human epidermal melanocytes. Subsequent functional enrichment analysis identified the GRIN2C gene as a novel candidate for further investigation. Upregulation of GRIN2C was observed in a panel of melanoma cell lines, confirming the results of our high-throughput analysis. Strikingly, silencing of GRIN2C markedly reduced viability and clonogenicity of melanoma cells. Furthermore, a pharmacological inhibitor of GRIN2C ion channels (GluN2C) potently killed melanoma cells with minimal effects on normal melanocytes. Killing of melanoma cells by inhibition of GluN2C was not due to induction of apoptosis, since a general caspase inhibitor Z-VAD-FMK failed to rescue the cells. In contrast, treatment with the antioxidants Ferrostatin-1 and Liproxstatin-1 subverted cell death induced by GluN2C inhibition, suggesting that killing of melanoma cells is primarily due to induction of ferroptosis by increased reactive oxygen species (ROS). Collectively, these results uncover a potential role for GluN2C ion channels in the pathogenesis of melanoma and suggest that these ion channels may represent a promising target in the treatment of melanoma.