Cutaneous melanoma is one of the most lethal cancers because of its increased rate of metastasis and resistance to available therapeutic options. Early studies indicate that metformin has beneficial effects on some types of cancer, including melanoma. To clarify knowledge of the mechanism of action of metformin on this disease, two treatment-based approaches are presented using metformin on melanoma progression: an in-vitro and an in-vivo model. The in-vitro assay was performed for two experimental treatment periods (24 and 48 h) at different metformin concentrations. The results showed that metformin decreased cell viability, reduced proliferation, and apoptosis was a major event 48 h after treating B16F10 cells. Oxidative stress was characterized by the decrease in total thiol antioxidants immediately following 24 h of metformin treatment and showed an increase in lipid peroxidation. The in-vivo model was performed by injecting B16F10 cells into the subcutaneous of C57/BL6 mice. Treatment with metformin began on day 3 and on day 14, the mice were killed. Treatment of mice with metformin reduced tumor growth by 54% of its original volume compared with nontreatment. The decrease in systemic vascular endothelial growth factor, restoration of antioxidants glutathione and catalase, and normal levels of lipid peroxidation indicate an improved outcome for melanoma following metformin treatment, meeting a need for new strategies in the treatment of melanoma.