ObjectiveTo conduct a systematical evaluation and meta-analysis of the relation between serum total cholesterol (TC) level and the risk of gastric cancer. MethodsThe PubMed, Embase, Web of Science, and Cochrane Library databases were searched from inception to March 5, 2023. Two independent reviewers performed the literature search, identification, and screening, as well as performed the quality assessment and data extraction. ResultsA total of 12 studies with 5 143 671 participants and 40 551 patients with gastric cancer were included in the meta-analysis. The results of meta analysis showed that 9 studies reported that the elevated serum TC level decreased the risk of gastric cancer [OR (95%CI) was 0.91 (0.85, 0.98)], and 5 studies reported that the decreased serum TC level increased the risk of gastric cancer [OR (95%CI) was 1.93 (1.17, 3.18)]. Also the results of the subgroup analyses showed that the decreased serum TC level increased the risk of gastric cancer in the studies with cohort study, larger overall sample sizes and gastric cancer sample sizes, with longer duration of follow-up, and in those with habits of alcohol and smoking [0.89 (0.87, 0.92), 0.90 (0.87, 0.94), 0.90 (0.87, 0.93), 0.86 (0.82, 0.90), 0.90 (0.87, 0.93), and 0.90 (0.87, 0.93), respectively] , which was consistent with the overall results. In contrast, there was no statistical difference in the relation between the elevated serum TC level decreased the risk of gastric cancer between male and female patients in the gender subgroup. ConclusionsThe results of this systematical evaluation and meta-analysis suggest that serum TC level [135–294 mg/dL (3.49–7.62 mmol/L)] may be a protective factor for gastric carcinogenesis. The risk of gastric carcinogenesis may be increased when serum TC level decreases, and this change is a long-term and insidious process.