Oxygen-ozone (O2O3) therapy is a spreading intervention proposed to reduce pain intensity and improve physical function in patients with musculoskeletal conditions. The biological effects of O2O3 are strictly related to its biochemical properties. It induces moderate oxidative stress and promotes the activation of specific transcriptional pathways related to endogenous radical scavengers. In this context, O2O3 therapy promotes immune modulation and inflammatory regulation that might potentially have a key role in the management of patients with musculoskeletal disorders. Interestingly, in recent years a growing number of studies have been showing promising results of O2O3 local therapy in different conditions, including low back pain, neck pain, knee osteoarthritis, and temporomandibular disorders. Due to its positive effects in terms of not only pain management but also functional improvement, it has been suggested that this promising therapy might be effectively integrated into a comprehensive rehabilitation approach to musculoskeletal disorders. Despite these considerations, several questions remain open about the effects of O2O3 combined with other conventional approaches. The aim of this narrative review was therefore to summarize the state of the art of O2O3 local therapy from a rehabilitation perspective, underlining its potential synergisms with other techniques in a multitarget rehabilitation approach to musculoskeletal disorders.