This observational study explored the association between proton pump inhibitor (PPI) and histamine-2 receptor antagonist (H2RA) use and the risk of chronic kidney disease (CKD). Using the National Health Insurance Service-National Sample Cohort (NHIS-NSC) and six-hospital electronic health record (EHR) databases, CKD incidence was analyzed among PPI and H2RA users. Propensity score matching was used to balance baseline characteristics, with 1,869 subjects each in the PPI and H2RA groups from the NHIS-NSC, and 5,967 in EHR databases. CKD incidence was similar for both groups (5.72/1000 person-years vs. 7.57/1000 person-years; HR = 0.68; 95% CI, 0.35–1.30). A meta-analysis of the EHR databases showed no significant increased CKD risk associated with PPI use (HR = 1.03, 95% CI: 0.87–1.23). These results suggest PPI use may not increase CKD risk compared to H2RA use, but the potential role of PPI-induced CKD needs further research. Clinicians should consider this when prescribing long-term PPI therapy.