Although radiation therapy plays a crucial role in cancer treatment, and techniques have improved continuously, irradiation induces side effects in healthy tissue. Radiation cystitis is a potential complication following the therapeutic irradiation of pelvic cancers and negatively impacts patients’ quality of life (QoL). To date, no effective treatment is available, and this toxicity remains a therapeutic challenge. In recent times, stem cell-based therapy, particularly the use of mesenchymal stem cells (MSC), has gained attention in tissue repair and regeneration due to their easy accessibility and their ability to differentiate into several tissue types, modulate the immune system and secrete substances that help nearby cells grow and heal. In this review, we will summarize the pathophysiological mechanisms of radiation-induced injury to normal tissues, including radiation cystitis (RC). We will then discuss the therapeutic potential and limitations of MSCs and their derivatives, including packaged conditioned media and extracellular vesicles, in the management of radiotoxicity and RC.