Hypoxia in tumors is known to trigger the pro-survival pathways such as autophagy. Systemic proopiomelanocortin (POMC) gene therapy suppresses melanoma through apoptosis induction and neovascularization blockage. In this study, we investigated the crosstalk between autophagic and apoptotic signaling in POMC-mediated melanoma suppression. By histological and immunoblot analysis, it was shown that POMC-treated melanoma tissues exhibited the prominent LC3 immunostaining, which was correlated with reduced CD31-positive tumor vascularization. Such autophagy induction could be recapitulated in melanoma cells receiving POMC gene delivery and hypoxia-mimicking agent cobalt chloride (CoCl2). We then utilized the POMC-derived peptide α-MSH with CoCl2 to elicit the autophagy as well as apoptosis in cultured melanoma cells. To delineate the role of autophagy during cell death, application of autophagy-inducer rapamycin enhanced, whereas autophagy inhibitor 3-MA attenuated, the α-MSH-induced apoptosis in melanoma cells. Genetic silencing of ATG5, an autophagy regulator, by RNA interference perturbed the α-MSH-induced apoptosis in melanoma cells. Finally, it was delineated that α-MSH stimulated the HIF-1α signaling as well as the expression of BNIP3/BNIP3L, thereby promoting the autophagy and apoptosis in melanoma cells. Therefore, the present study unveiled a unique function of autophagy in promoting cell death during POMC-mediated melanoma suppression via α-MSH/HIF-1α/BNIP3/BNIP3L signaling pathway.