SIRT6, a member of NAD positivity-dependent class III deacetylase sirtuin family, played versatile roles in human cancers. However, the expression and biological function of SIRT6 in gastric cancer (GC) remain to be investigated. In this study, we found that SIRT6 expression level was decreased in gastric cancer tissues and cell lines. Decreased SIRT6 expression was associated with unfavorable clinical parameters including tumor differentiation, tumor size and TNM stage. Importantly, decreased level of SIRT6 was associated with decreased rate of overall survival (OS) and disease‑free survival (DFS). Functionally, overexpression of SIRT6 in both BGC823 and SGC7901 cells inhibited cell viability and proliferation of GC cells. Furthermore, overexpression of SIRT6 in both BGC823 and SGC7901 cells prevented the cell cycle progress and increased cell apoptosis. In vivo experiments demonstrated that forced expression of SIRT6 in SGC-7901 cells inhibited the growth of SGC7901 cells in nude mice. Furthermore, the IHC staining for GC tissues showed that expression level of SIRT6 was decreased in GC tissues while the expression level of p-STAT3 was increased in GC tissues. GC tissues with high SIRT6 level showed significantly decreased level of p-STAT3. Mechanically, we demonstrated that SIRT6 blocked the activation of JAK2/STAT3 and inhibited the expression of cyclin D1 and Bcl2 which were downstream targets of JAK2/STAT3 pathway. Taken together, this study indicates that SIRT6 inhibits the growth of gastric cancer by inhibiting JAK2/STAT3 pathway.