Objectives: We sought to determine whether interventions that target work organization or the psychosocial work environment are effective in preventing or reducing work-related musculoskeletal disorders (WMSD) compared to usual work. Methods: We systematically reviewed the 2000–2015 English and French language scientific literature, including studies evaluating the effectiveness of an organizational or psychosocial work intervention on incidence, prevalence or intensity of work-related musculoskeletal pain or disorders in the neck, shoulders, upper limbs and/or back or of work absence due to such problems, among non-sick-listed workers. We excluded rehabilitation and individual-level behavioral interventions and studies with >50% attrition. We analyzed medium- and high-quality studies and synthesized the evidence using the Grading of Recommendations Assessment, Development & Evaluation (GRADE) approach. An analysis of key workplace intervention elements supplemented interpretation of results. Results: We identified 884 articles; 28 met selection criteria, yielding 2 high-quality, 10 medium-quality and 16 low-quality studies. There was moderate evidence that supplementary breaks, compared to conventional break schedules, are effective in reducing symptom intensity in various body regions. Evidence was low- to very low-quality for other interventions, primarily due to risk of bias related to study design, high attrition rates, co-interventions, and insensitive indicators. Most interventions lacked key intervention elements, such as work activity analysis and ergonomist guidance during implementation, but the relation of these elements to intervention effectiveness or ineffectiveness remains to be demonstrated. Conclusions: Targeting work–rest cycles may reduce WMSD. Better quality studies are needed to allow definitive conclusions to be drawn on the effectiveness of other work organizational or psychosocial interventions to prevent or reduce WMSD.