Background: Bladder pain syndrome (BPS), also known as interstitial cystitis, is a chronic condition characterized by pelvic pain and urinary symptoms that severely impair patients’ quality of life (QoL). The current therapeutic options often yield suboptimal results, prompting interest in complementary treatments. Systemic ozone therapy, known for its anti-inflammatory, immunomodulatory, and analgesic effects, may represent a promising adjunctive treatment for BPS. Objective: This study aimed to evaluate the efficacy and safety of systemic ozone therapy in improving the self-perceived QoL in patients with BPS. Methods: The retrospective observational study included 40 patients diagnosed with BPS according to ESSIC criteria. All patients underwent systemic ozone therapy administered through hemotransfusion, following a standardized protocol. Outcomes were assessed using the Short Form (SF)-36 questionnaire for QoL and the Global Response Assessment (GRA) for subjective treatment efficacy. Statistical analyses evaluated changes in SF-36 domain scores and their correlation with GRA results. Results: Patients demonstrated significant improvement across all domains of the SF-36 questionnaire, with the most notable gains observed in physical functioning and mental health. The mean GRA score confirmed patient-perceived effectiveness, showing a strong positive correlation with SF-36 improvements (p<0.05). No adverse events or complications were found during the study. Conclusion: Systemic ozone therapy appears to be a safe and effective complementary treatment for BPS, significantly enhancing patients’ QoL across multiple domains. While these findings are promising, randomized controlled trials are needed to validate the results and further explore underlying mechanisms, such as the role of ozone in modulating inflammatory and neural pathways.