BackgroundDepression affects a significant portion of the global adult population, with chronic pain patients being particularly susceptible to severe depression. Pain and mental illness contribute to an imbalance in the autonomic nervous system, affecting heart function. Myofascial release promises to improve mental and physical health by addressing fascial dysfunctions. ObjectiveThis study aims to investigate the influence of myofascial release on emotional states and autonomic nervous system functioning in individuals with chronic neck pain and depression. Additionally, it seeks to evaluate the myofascial release effect on fascial properties, pain intensity and sensitivity, and cervical spine range of motion. MethodExperimental Study. ResultThe study revealed significant enhancements in the myofascial release group, such as a substantial reduction in pain perception and stiffness, increased range of motion of the cervical spine, heart rate variability, positive affect, and pressure pain threshold. The effect sizes of these improvements ranged from small to large. No significant differences were observed in elasticity and tone. ConclusionThe findings suggest that myofascial release has a positive impact on individuals with chronic neck pain and depression, particularly in reducing pain intensity. Integrating myofascial release into treatment approaches may be beneficial. However, further research is needed to confirm and expand upon these findings, explore long-term effects, and better understand the clinical significance of certain outcomes. Trial registrationhttp://www.osf.io, doi.org/10.17605/OSF.IO/6F5RS