Proton pump inhibitors (PPIs) are widely prescribed for upper gastrointestinal disorders (UGID), but concerns exist about neurological adverse effects associated with long-term PPI use. This study aimed to evaluate the association between PPI use and the risk of Parkinson’s disease (PD). We conducted a retrospective cohort study using the National Health Insurance Service database, including patients aged ≥40 years with UGID. PPI users were compared with non-users using propensity score matching. Hazard ratios (HRs) and 95% confidence intervals (CIs) for PD were estimated using Cox proportional hazards models. Analyses were stratified by cumulative duration and cumulative defined daily dose (cDDD) of PPIs, with a sensitivity analysis restricted to individuals aged ≥50 years. Overall PPI use was not significantly associated with PD risk (HR 1.03, 95% CI 0.94–1.09). However, PD risk tended to increase with longer cumulative duration of PPI use (HR 0.96 for <30 days, 1.00 for 30–89 days, and 1.03 for 90–179 days), with a significantly increased risk observed at ≥180 days (HR 1.20, 95% CI 1.04–1.38). A similar increase was observed for cumulative dose ≥180 cDDD (HR 1.20, 95% CI 1.02–1.40). Similar patterns were observed in individuals aged ≥50 years. Kaplan–Meier curves also showed a higher cumulative incidence of PD among long-term PPI users. These findings suggest that prolonged or high cumulative exposure to PPIs may be associated with an increased risk of PD.