Background Proton pump inhibitors (PPIs) are widely used to treat digestive system diseases. Previous studies have suggested conflicting results between PPIs treatment and digestive tract cancers (DTCs). We utilized the FDA Adverse Event Reporting System (FAERS) database to assess the effect of PPIs use on DTCs through data mining. Method This study examined the association between six PPI agents and DTCs by mining the FAERS database from January 2004 to September 2021 by using Open Vigil 2.1. The reporting odds ratio (ROR) with 95% confidence intervals (CIs) was used to detect statistically significant associations between PPIs and DTCs. High Level Terms (HLTs) and Preferred Terms (PTs) were defined by the Medical Dictionary for Regulatory Activities 24.0 (MedDRA24.0). Result A total of 2553 DTCs adverse event reports were screened, with positive signals obtained from gastric neoplasms malignant (GNM) (ROR: 1.09, 95% CI: 1.01-1.18) and bile duct neoplasms malignant (BDNM) (ROR: 1.80, 95% CI: 1.44-2.25). Esomeprazole showed the strongest signal (ROR: 1.85, 95% CI: 1.66-2.06) for GNM, while rabeprazole for BDNM (ROR: 2.94, 95% CI: 1.32-6.56), and female PPI users had a higher risk of BDNM (ROR: 2.44, 95% CI: 1.77-3.35). Among Subordinate PTs, adenocarcinoma gastric, and the combination of “bile duct cancer” and “cholangiocarcinoma” were highly associated with PPIs use. Conclusion By mining the FAERS database, we provided important clues for the association between PPIs use and DTCs risk.