A substantial evidence-practice gap exists between healthcare professionals learning about the biopsychosocial model of pain and adopting this model in clinical practice. This review aimed to explore the barriers and enablers that influence the application of a biopsychosocial approach to musculoskeletal pain in practice, from the clinicians’ perspective. Qualitative evidence synthesis was used. Four electronic databases (CINAHL, EMBASE. MEDLINE, PsycINFO) were searched. Primary qualitative studies were included if they investigated the experiences of primary healthcare professionals using a biopsychosocial model of musculoskeletal pain care in outpatient settings, or their perceptions towards biopsychosocial-oriented clinical practice guidelines. After screening 6571 abstracts, 77 full text articles were retrieved. Twenty-five studies met the eligibility criteria, reporting the experiences of 413 healthcare professionals (including general practitioners, physiotherapists and others) spanning 11 countries. Three metathemes were identified that impact the adoption of the biopsychosocial model across the whole-of-health: (1) at the micro-level, healthcare professionals’ personal factors, knowledge and skills, and their misconceptions of clinical practice guidelines, perception of patients’ factors and time; (2) at the meso-level, clinical practice guideline formulation, community factors, funding models, health service provision, resourcing issues and workforce training issues; and (3) at the macro-level, health policy, organizational and social factors. Synthesized data revealed multi-level (whole-of-health) barriers and enablers to health professionals adopting a biopsychosocial model of pain into practice. Awareness of these multi-level factors may help inform pre-implementation preparedness and support more effective implementation of the biopsychosocial model of musculoskeletal pain into clinical practice.