Melanoma is a highly aggressive type of skin cancer. The development of diverse resistance mechanisms and severe adverse effects significantly limit the efficiency of current therapeutic approaches. Identification of the new therapeutic targets involved in the pathogenesis will benefit the development of novel therapeutic strategies. The deubiquitinase ubiquitin-specific protease-7, a potential target for cancer treatment, is deregulated in types of cancer, but its role in melanoma is still unclear. We investigated the role and the inhibitor P22077 of ubiquitin-specific protease-7 in melanoma treatment. We found that ubiquitin-specific protease-7 was overexpressed and correlated with poor prognosis in melanoma. Further, pharmacological inhibition of ubiquitin-specific protease-7 by P22077 can effectively inhibit proliferation, and induce cell cycle arrest and apoptosis via ROS accumulation-induced DNA damage in melanoma cells. Inhibition of ubiquitin-specific protease-7 by P22077 also inhibits melanoma tumour growth in vivo. Moreover, inhibition of ubiquitin-specific protease-7 prevented migration and invasion of melanoma cells in vitro and in vivo by decreasing the Wnt/β-catenin signalling pathway. Taken together, our study revealed that ubiquitin-specific protease-7 acted as an oncogene involved in melanoma cell proliferation and metastasis. Therefore, ubiquitin-specific protease-7 may serve as potential candidates for the treatment of melanoma.