Background: It has been reported that prostate stem cell antigen (PSCA) is overexpressed in certain cancer types and confers poor prognoses. The rs2294008 (C/T) polymorphism of PSCA is considered to be associated with risk for gastric, bladder, and colorectal cancers; however, these studies have produced inconsistent results, so we performed this meta-analysis to verify the association between the PSCA rs2294008 (C/T) polymorphism and cancer risk. Methods: A systematic literature search was performed using PubMed, EMBASE, and the Chinese National Knowledge Infrastructure, through October 20, 2022 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association between the PSCA rs2294008 (C/T) polymorphism and cancer risk. In addition, we explored PSCA mRNA expression in cancers through online databases. Results: In total, 45 articles met our inclusion criteria and were analyzed, including 37,586 cancer cases and 51,197 non-cancer controls. Except in the recessive model, the pooled effect indicated the PSCA rs2294008 T allele was associated with an increased overall cancer risk (T vs. C: OR = 1.120, 95% CI = 1.056-1.188, p < 0.01; TT vs. CC: OR = 1.206, 95% CI = 1.066-1.364, p = 0.03; CT vs. CC: OR = 1.249, 95% CI = 1.151-1.356, p < 0.01; [CT+TT] vs. CC: OR = 1.248, 95% CI = 1.147-1.359, p < 0.01; TT vs. [CT+CC]: OR = 1.051, 95% CI = 0.954-1.156, p = 0.314). In the subgroup analysis, there were significant associations between the rs2294008 T allele and increased risk of bladder and gastric cancer. Two different online tools were used to explore the PSCA mRNA levels in cancer and the corresponding normal adjacent tissues. We found that expression of PSCA was significantly lower in gastric cancer patients. Conclusions: The PSCA rs2294008 T polymorphism is related to increased cancer susceptibility, especially for gastric and bladder cancers. This polymorphism results in a decreased PSCA expression level in gastric cancer.