Proton pump inhibitors (PPIs) have become one of the most commonly prescribed medications worldwide. Although PPIs are generally considered safe and well‐tolerated, studies indicate that they may be associated with certain cancer types. This study aimed to examine the association between the use of PPIs and the risk of hepatobiliary cancer using newly available evidence. Effect sizes with their variances and other characteristics were extracted from 10 eligible studies appraised from combined search results published up to September 16, 2022, from PubMed, Cochrane library, and Google Scholar. Sensitivity and trial sequential analyses were also conducted to ensure the robustness of the synthesized results. The estimated pooled relative risk for this study was 1.69 (95% CI 1.44–1.98), and the test result for the overall effect was p < .01 under a zero effect null hypothesis. According to the sensitivity analysis, the results should be robust. A significant association was observed between the use of PPIs and the risk of developing hepatobiliary cancer. The use of PPIs should be determined by prescribers as either absolutely or conditionally necessary, and, when possible, a patient's perspective should be considered in the decision‐making process for PPI use.