Musculoskeletal disorders (MSD) are a crucial issue in current literature due to their impact on physical function, social, and economic costs. Rehabilitation plays a pivotal role in the therapeutic management of these disabling conditions with growing evidence underlining positive effects in improving functional outcomes. However, to date, several questions are still open about the mechanisms underpinning functional improvements while recent research is now focusing on a deeper understanding of the biophysical processes underpinning the macroscopical effects of these treatments. Thus, this narrative review aims at providing a comprehensive overview about the state of the art of biophysical dimensions of currently available treatments for MSD. PubMed, Scopus, CENTRAL, PEDro, and Web of Science were searched between March 2022 and October 2022 for in vitro and in vivo studies, clinical trials, systematic reviews, and meta-analysis addressing the issue of biophysics-based approach in rehabilitation of MSD. Our findings showed that a biophysical approach might be integrated into regenerative rehabilitation, aiming at enhancing regenerative processes by mechanical and biophysical stimuli. In addition, a biophysical-based approach has been proposed to improve knowledge about several instrumental physical therapies, including shock wave therapies, low-level laser therapy, ultrasound, short-wave diathermy, electrical stimulation, pulsed electromagnetic field, and vibration therapy. In accordance, emerging research is now focusing on the biophysical properties of several medical procedures to improve pain management in patients with MSD. Taken together, our results showed promising results of the integration of a biophysical-based approach in rehabilitation, albeit several limitations currently limit its implementation in routine clinical setting. Unfortunately, the state of the art is still inconclusive, and the low quality of clinical studies based on the biophysical approach did not provide clear treatment protocols. Further studies are needed to promote a precise rehabilitation approach targeting biological modification and enhancing the functional improvement of patients with MSDs.