AbstractSIRT2 is a member of the mammalian sirtuin family (SIRT1‐7). As compared with other sirtuins, SIRT2 is found primarily in the cytoplasm. It regulates multiple physiological processes. However, the precise role of SIRT2 in skin cancer remains unclear. Here, we show that SIRT2 is downregulated in human skin cancer as compared with normal skin. SIRT2 deletion increases tumor growth in mice. SIRT2 knockdown upregulates the stem cell marker Keratin 19 (K19) in keratinocytes. In mice, SIRT2 deletion up‐regulates K19 and K15 while it down‐regulates the differentiation marker Loricrin in both normal skin and tumors. In skin tumors but not normal skin, SIRT2 deletion up‐regulates the stem cell marker CD34 and increases the number of Ki67‐positive cells. These findings indicate that SIRT2 is a tumor suppressor in the skin. Our findings add new insights into the role of SIRT2 in the molecular pathogenesis of skin cancer.