The majority of metastatic melanomas are resistant to different chemotherapeutic agents, consequently, the search for novel anti-melanoma agents and adjuvant is urgent. Here, we found that 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), an inhibitor of glycosphingolipid biosynthesis, enhanced curcumin-induced cell growth inhibition and apoptosis in two melanoma cell lines (WM-115 and B16). PDMP facilitated curcumin-induced ceramide accumulation; the latter contributed to melanoma cell apoptosis. PDMP also dramatically enhanced curcumin-induced c-Jun N-terminal kinase activation, which was important to melanoma cell apoptosis. Meanwhile, curcumin plus PDMP treatment largely inhibited the activation of pro-survival PI3K/AKT signal pathway. In conclusion, PDMP-sensitized curcumin-induced melanoma cell growth inhibition and apoptosis in vitro due to changes of multiple signal events. Combining PDMP with curcumin may represent a new therapeutic intervention against melanoma.