Musculoskeletal disorders encompass a wide range of conditions that impact the bones, joints, muscles, and connective tissues within the body. Despite the ongoing debate on toxicity and administration, ozone demonstrated promise in managing several musculoskeletal disorders, modulating pain and inflammation. A literature search was conducted. The research design, methods, findings, and conclusions of the studies were then examined to evaluate the physiological effects, clinical application, controversies, and safety of the application of ozone in musculoskeletal medicine. Ozone application demonstrates considerable therapeutic applications in the management of musculoskeletal disorders, including fractures, osteoarthritis, and chronic pain syndromes. Despite these advantages, studies have raised concerns regarding its potential toxicity and emphasized the importance of adhering to stringent administration protocols to ensure safety. Additionally, heterogeneities in patient reactions and hazards from oxidizing agents were observed. Given its anti-inflammatory and analgesic qualities, ozone therapy holds potential in the management of several musculoskeletal disorders. Additional high-quality research with long follow-up is required to refine indications, efficacy and safety profile. Finally, for wider clinical acceptability and utilization, the development of international recommendations is essential.