Melanoma is the most dangerous form of skin cancer; more than 1,700 Australians die from melanoma each year. Metastasis is the reason melanoma is so deadly. A number of studies have linked vitamin D status to melanoma risk and outcome. Vitamin D synthesis is initiated upon UVB exposure of 7-dehydrocholesterol in skin cells and results in formation of the active metabolite 1,25-dihydroxyvitamin D3 (1,25D). Previous studies in our lab have shown that 1,25D can significantly (p < 0.001) reduce melanoma cell migration in vitro. We now show this effect in a time course and furthermore demonstrate this effect in a 3D in vitro model. N-myc downstream-regulated gene 1 (NDRG1) is a metastasis suppressor that is involved in many signaling pathways, such as p53 and PI3K/AKT. Previous in vitro studies in our lab have demonstrated a significant (p < 0.05, p < 0.01) 1,25D-induced increase in NDRG1 levels in two melanoma cell lines. We now show the time course for this effect and furthermore demonstrate this in another five human melanoma (including metastatic) cell lines. 1,25D exerts its effects via the vitamin D receptor (VDR). Herein we demonstrate that 1,25D can up-regulate NDRG1 either dependently or independently of the VDR and affect cell migration and angiogenesis. By up-regulating the metastasis suppressor NDRG1, 1,25D may act to inhibit melanoma metastasis, stop progression to angiogenesis and contribute to better outcomes for melanoma.