Owing to its highly heterogeneous molecular landscape, bladder cancer (BlCa) is still characterized by non-personalized treatment and lifelong surveillance. Motivated by our previous findings on miR-143/145 value in disease prognosis, we have studied the underlying epigenetic regulation of the miR-143/145 cluster in BlCa. Expression and DNA methylation of miR-143/145 cluster were analyzed in our screening (n = 162) and The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA; n = 412) cohorts. Survival analysis was performed using tumor relapse and progression as clinical endpoints for non-muscle-invasive bladder cancer (NMIBC; TaT1), while disease progression and patients' death were used for muscle-invasive bladder cancer (MIBC; T2-T4). TCGA-BLCA served as validation cohort. Bootstrap analysis was carried out for internal validation, while decision curve analysis was used to evaluate clinical benefit. TCGA-BLCA and screening cohorts highlighted core promoter as the pivotal, epigenetic regulatory region on cluster's expression. Lower methylation of core promoter was associated with aggressive disease phenotype, higher risk for NMIBC short-term progression, and poor MIBC survival. methylation-fitted multivariate models with established disease markers clearly enhanced patients' risk stratification and prediction of treatment outcome. core promoter methylation was identified as a potent epigenetic regulator of miR-143/145 cluster, supporting modern personalized risk stratification and management in BlCa.