We aimed to evaluate the correlation between serum sirtuin 6 (sirt6) level and clinicopathological characteristics and prognosis of gastric cancer (GC) patients. The serum sirt6 levels of subjects (135 cases of GC, 68 cases of atrophic gastritis, 60 cases of healthy controls) were analyzed by enzyme-linked immunosorbent assay. The predictive and prognostic values of sirt6 serum level for GC were determined by performing receiver operating characteristic curve (ROC), Kaplan-Meier analysis, as well as univariate and multivariate Cox regression, respectively. GC patients showed lower sirt6 serum levels than that of atrophic gastritis patients and healthy control. Taking the healthy control as a reference, the area under the ROC curve (AUC) of sirt6 serum level for diagnosing GC was 0.955 with a sensitivity of 91.85% and a specificity of 90.0%. Based on ROC analysis using atrophic gastritis as the state variable, serum sirt6 had a high diagnostic efficiency for GC (AUC = 0.754). Serum sirt6 was related to the clinicopathological features (tumor size, Lauren's classification, tumor node metastasis staging, lymph node metastasis) and overall survival (log-rank χ2 = 12.22, P < .001). The AUC of serum sirt6 predicting death in GC patients was 0.731. At the optimal cutoff value (16.83 ng/mL), the sensitivity and specificity of sirt6 were 59.57% and 79.55%, respectively. Moreover, lower sirt6 level as independent risk factor was revealed to affect prognosis of GC patients (P = .018). Serum sirt6 level was positively associated with the tumor stage and metastasis conditions, which could be served as diagnostic and predictive biomarkers in GC.