Previous experiments in the syngeneic, murine, and subcutaneous model of malignant melanoma and human melanoma cells showed that treatment by recombinant human (rh) Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) markedly reduced the volume of tumors, improved survival, and inhibited invasiveness. In this report, the impact of ARSB on the progression of metastatic, pulmonary B16F10 melanomas in C57BL/6J mice is addressed, and the underlying apoptotic mechanism by which ARSB inhibits melanoma growth is identified. Exogenous ARSB, which has mannose 6-phosphate attachments, acts through insulin-like growth factor 2 receptor (IGF2R), a cation-independent mannose-6-phosphate receptor, and increases expression of constitutive photomorphogenic protein (COP)1. Expression of COP1, an E3 ubiquitin ligase, is increased by a decline in phospho(Ser473)-AKT1 and an increase in nuclear FOXO3a. ARSB-induced declines in carbohydrate sulfotransferase (CHST)15 expression and in transmembrane receptor tyrosine kinase-like orphan receptor 1 (ROR1) activation mediate the decline in phospho(Ser473)-AKT1. Inverse effects of rhARSB and ARSB knockdown on phospho(Ser473)-AKT1 indicate that ARSB acts as a tumor suppressor and that a decline in ARSB is pro-oncogenic. COP1, which inhibits ultraviolet-B stimulated growth in plants, suppresses nuclear ETS1 and ETS1-mediated expression of BCL2 in the murine melanomas and in human melanoma cells. These effects increase cytoplasmic cytochrome c, caspase-3/7 activation, and apoptosis. Since UVB exposure is recognized as a significant etiological factor in melanoma, identification of COP1 as an inhibitor of melanoma growth suggests the underlying presence of an ARSB-initiated growth inhibitory mechanism, analogous to that in plants, which contributes to the regulation of melanoma progression.