Oxygen-ozone (O<sub>3</sub>) therapy serves as an alternative medical technique that increases the oxygen in the body along with the introduction of O<sub>3</sub>. O<sub>3</sub> therapy has finally reached a level where the biological mechanisms of action have been understood, showing that they are in the domain of physiology, biochemistry, and pharmacology. Few clinical applications have been reviewed here as well as exemplifying that O<sub>3</sub> therapy is particularly useful in musculoskeletal disorders. In the therapeutic range, O<sub>3</sub> can be used as a more effective and safe substitute of standard medications. O<sub>3</sub> therapy has been used for many years for its ability to inactivate various viruses, cancer, and acquired immune deficiency syndrome but is now making strides in the treatment of musculoskeletal disorders such as rheumatoid arthritis, lumbar facet joint syndrome, subacromial bursitis, carpal tunnel syndrome, osteoarthritis, hip bursitis, shoulder adhesive capsulitis, herniated disc, and temporomandibular joint disorder.