Globally, mental and musculoskeletal disorders present with high prevalence, disease burden, and comorbidity. In order to improve the quality of care for patients with persistent physical and comorbid mental health conditions, person-centered care approaches addressing psychosocial factors are currently advocated. Central to successful person-centered care is a multidisciplinary collaboration between mental health and musculoskeletal specialists underpinned by a robust therapeutic alliance. Such a collaborative approach might be found in osteopathy, which is typically utilized to treat patients with musculoskeletal disorders but may arguably also benefit mental health outcomes. However, research and practice exploring the reputed effect of osteopathy on patients with mental health problems lack a robust framework. In this hypothesis and theory article, we build upon research from embodied cognition, predictive coding, interoception, and osteopathy to propose an embodied, predictive and interoceptive framework that underpins osteopathic person-centered care for individuals with persistent physical and comorbid mental health problems. Based on the premise that, for example, chronic pain and comorbid depression are underlined by overly precise predictions or imprecise sensory information, we hypothesize that osteopathic treatment may generate strong interoceptive prediction errors that update the generative model underpinning the experience of pain and depression. Thus, physical and mental symptoms may be reduced through active and perceptual inference. We discuss how these theoretical perspectives can inform future research into osteopathy and mental health to reduce the burden of comorbid psychological factors in patients with persistent physical symptoms and support person-centered multidisciplinary care in mental health.