The potential association between red yeast rice (RYR) use and the risk of end-stage renal disease (ESRD) remains unclear. This study aimed to evaluate the risk of ESRD in patients received RYR compared to those who were not. A retrospective cohort study was conducted using Taiwan’s national insurance claims data from 2010 to 2014, including 67,876 RYR users and 90,836 lovastatin users, with follow-up until 2019. ESRD incidence was compared between cohorts using multiple Cox regressions and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). During follow-up, ESRD incidence was 0.9 per 1,000 person-years in RYR users compared to 3.7 per 1,000 person-years in non-users (HR 0.33, 95% CI 0.30-0.37). The association between RYR and ESRD risk was existed in various subgroups. A dose-dependent reduction in ESRD risk was observed with increasing RYR prescriptions. Sensitivity analysis, excluding ESRD cases within the initial six months, confirmed a persistent association between RYR use and reduced ESRD risk (HR 0.61, 95% CI 0.27-0.57). RYR use was associated with a lower risk of ESRD, however, medication adherence warrant cautious interpretation. Further randomized controlled trials are needed to clarify RYR’s role in slowing kidney disease progression.