Melanoma is the most life-threatening skin cancer with increasing incidence around the world. Although recent advances in targeted therapy and immunotherapy have brought revolutionary progress of the treatment outcome, the survival of patients with advanced melanoma remains unoptimistic, and metastatic melanoma is still an incurable disease. Therefore, to further understand the mechanism underlying melanoma pathogenesis could be helpful for developing novel therapeutic strategy. A20 is a crucial ubiquitin-editing enzyme implicated immunity regulation, inflammatory responses and cancer pathogenesis. Herein, we report that A20 played an oncogenic role in melanoma. We first found that the expression of A20 was significantly up-regulated in melanoma cell lines. Then, we showed that knockdown of A20 suppressed melanoma cell proliferation in vitro and melanoma growth in vivo through the regulation of cell-cycle progression. Moreover, A20 could potentiate the invasive and migratory capacities of melanoma cell in vitro and melanoma metastasis in vivo by promoting epithelial-mesenchymal transition (EMT). Mechanistically, we found that Akt activation mediated the oncogenic effect of A20 on melanoma development, with the involvement of glycolysis. What's more, the up-regulation of A20 conferred the acquired resistance to Vemurafenib in BRAF-mutant melanoma. Taken together, we demonstrated that up-regulated A20 promoted melanoma progression via the activation of Akt pathway, and that A20 could be exploited as a potential therapeutic target for melanoma treatment.