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Background Radiation cystitis (RC) is a major complication of pelvic radiotherapy, leading to inflammation, vascular damage, and fibrosis. While mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show promise in regenerative medicine, their therapeutic effects on RC remain unclear. This study evaluates the efficacy of human umbilical cord MSC-EVs (huMSC-EVs) in mitigating Radiation-induced bladder damage. Methods Animal models of RC were established using 20 Gy pelvic irradiation. Forty-four female Sprague-Dawley rats were divided into four groups: negative control (NC, no radiation), positive control (PC, radiation only), local treatment (LT, huMSC-EVs injected into the bladder wall), and systemic treatment (ST, intravenous huMSC-EVs). Bladder function and compliance were assessed via metabolic cage and urodynamic studies (UDS) at 6 and 24 weeks. Histopathological changes and inflammatory cytokine levels were evaluated at multiple time points. Results Administration of huMSC-EVs significantly improved urinary frequency and hematuria. Histological analysis showed reduced urothelial disintegration and edema in the early phase, and improved urothelial integrity, reduced hyperplasia and vascular lesions, and restored bladder architecture in the late phase, in the treated groups. UDS demonstrated preserved bladder compliance and voiding efficiency in LT rats, with significantly higher voided volume ( p  < 0.01) and lower post-voiding residue ( p  < 0.05) compared to the PC group 24 weeks post-irradiation. Pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6 were markedly lowered and their levels were similar to the non-radiated NC group in LT-treated rats ( p  = 1.00, p  = 0.22, p  = 0.16), 24 weeks post-irradiation. Conclusions Local huMSC-EVs therapy effectively reduces RC-related bladder injury and preserves function, likely by modulating inflammatory response and epithelial regeneration. These findings highlight huMSC-EVs as a promising strategy to prevent chronic RC, warranting further clinical exploration.