Psychosocial factors, musculoskeletal disorders and work-related fatigue have adverse effects on individual nurses and place a substantial financial burden on health care. Evidence of an association has been reported in the literature, but no theoretical explanation has been published to date.To explore and develop a structural model to provide a theoretical explanation for this relationship.A cross-sectional study using data from 201 valid samples of emergency and critical care nurses across public hospitals in Brunei was performed via self-administered questionnaire. The structural equation model was assessed using partial least squares analysis.A valid and robust structural model was constructed. This revealed that 61.5% of the variance in chronic fatigue could be explained by psychosocial factors and musculoskeletal disorders pathways. Among the psychosocial factors, work-family conflict was identified as a key mediator for progression of musculoskeletal problems and subsequent fatigue through stress and burnout.This report provides a novel theoretical contribution to understanding the relationship between psychosocial factors, musculoskeletal disorders and work-related fatigue. These preliminary results may be useful for future studies on the development of work-related fatigue and musculoskeletal disorders, particularly the central role of work-family conflict.