Background. The impact of HR practices on nurses’ well-being the underlying mechanisms involved and the contextual factors which enhance or impede their success, are not fully clear. Purpose. This paper examines a moderated mediation model whereby high-involvement work practices are purported to reduce nurses’ burnout via psychological empowerment and colleague support is expected to moderate the mediating role of psychological empowerment in the high-involvement work practices-burnout link. Methodology/Approach. Structural Equation Modeling was employed on cross-sectional survey data collected from a large sample of nurses in Canada (N= 2,174). Results. The findings revealed that psychological empowerment partially mediated the association between high-involvement work practices and burnout while colleague support was directly associated with lower burnout rather than exerting a moderating effect. Conclusion. The study identifies the universality of high-involvement work practices in alleviating nurses’ burnout and highlights the important role of psychological empowerment as an explanatory variable. In addition, colleague support is an important yet independent predictor of nurses’ burnout. Practical Implications This study identifies a critical strategy, i.e. HIWPs, for hospital and nursing managers, that can be used to help protect against the perennial problem of nurse burnout and offers a more nuanced understanding of the underlying processes involved.