The Ser326Cys polymorphism in the human 8-oxogunaine DNA glycosylase (hOGG1) gene had been implicated in cancer susceptibility. Studies investigating the associations between the Ser326Cys polymorphism and digestion cancer susceptibility showed conflicting results. Therefore, a meta-analysis was performed to derive a more precise estimation of the relationship. We conducted a meta-analysis of 48 studies that included 12,073 cancer cases and 19,557 case-free controls. We assessed the strength of the association using odds ratios (ORs) with 95% confidence intervals (CIs). In our analysis, the hOGG1 Ser326Cys polymorphism was significantly associated with the risk of digestive system cancers (Cys/Cys vs. Ser/Ser: OR = 1.17, 95% CI = 1.00-1.35, P < 0.001; Cys/Cys vs. Cys/Ser + Ser/Ser: OR = 1.14, 95% CI = 1.00-1.29, P < 0.001). In subgroup analyses by cancer types, we found that the hOGG1 Ser326Cys polymorphism may increase hepatocellular cancer and colorectal cancer risks, but decrease the risk of oral cancer. These findings supported that hOGG1 Ser326Cys polymorphism may contribute to the susceptibility of digestive cancers.