Purpose: Radiation cystitis (RC), a severe inflammatory bladder condition, develops as a side effect of pelvic radiation therapy in cancer patients. There are currently no effective therapies to treat RC, in part from the lack of preclinical model systems. In this study, we developed a mouse model for RC and used a Small Animal Radiation Research Platform to simulate the targeted delivery of radiation as used with human patients. Methods and materials: To induce RC, C3H mice received a single radiation dose of 20 Gy delivered through 2 beams. Mice were subjected to weekly micturition measurements to assess changes in urinary frequency. At the end of the study, bladder tissues were processed for histology. Results: Radiation was well-tolerated; no change in weight was observed in the weeks after treatment, and there was no hair loss at the irradiation sites. Starting at 17 weeks after treatment, micturition frequency was significantly higher in irradiated mice versus control animals. Pathological changes include fibrosis, inflammation, urothelial thinning, and necrosis. At a site of severe insult, we observed telangiectasia, absence of uroplakin-3 and E-cadherin relocalization. Conclusions: We developed an RC model that mimics the human pathology and functional changes. Furthermore, radiation exposure attenuates the urothelial integrity long-term, allowing for potential continuous irritability of the bladder wall from exposure to urine. Future studies will focus on the underlying molecular changes associated with this condition and investigate novel treatment strategies.