In this study, we investigated the antitumor activity of axitinib, a selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases, against melanoma cells. Axitinib dose-dependently inhibited the proliferation and induced the apoptosis of B16F1 cells in vitro. In a mouse model of melanoma xenograft, axitinib significantly suppressed tumor growth and induced apoptosis of cells in tumor tissues at a dose of 25 mg/kg. In addition, axitinib suppressed the lung metastasis of melanoma cells and prolonged the life span of tumor-bearing mice. Axitinib also enhanced the proportion of CD8⁺ T cells and reduced the proportion of myeloid-derived suppressor cells in CD45.2⁺ cells, whereas the proportions of CD4⁺ T cells and Treg cells were not affected. The mRNA expressions of inducible nitric oxide synthases-2 and arginase-1, which were associated with the function of myeloid-derived suppressor cells in tumor tissues, were inhibited by axitinib. Moreover, axitinib suppressed the expressions of proinflammatory cytokines such as IL-6, TNF-α, and IFN-γ. Altogether, our results showed the unique antitumor mechanism of axitinib and provided useful information for its clinical application.