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Background: Healthcare literature suggests that leadership behavior has a profound impact on nurse work-related well-being. Yet, more research is needed to better conceptualize, measure, and analyse the concepts of leadership and well-being, and to understand the psychological mechanisms underlying this association. Combining Self-Determination and Job Demands-Resources theory, this study aims to investigate the association between engaging leadership and burnout and work engagement among nurses by focusing on two explanatory mechanisms: perceived job characteristics (job demands and resources) and intrinsic motivation. Methods: A cross-sectional survey of 1117 direct care nurses (response rate = 25%) from 13 general acute care hospitals in Belgium. Validated instruments were used to measure nurses' perceptions of engaging leadership, burnout, work engagement, intrinsic motivation and job demands and job resources. Structural equation modeling was performed to test the hypothesised model which assumed a serial mediation of job characteristics and intrinsic motivation in the relationship of engaging leadership with nurse work-related well-being. Results: Confirmatory factor analysis indicated a good fit of the measurement model. The findings offer support for the hypothesized model, indicating that engaging leadership is linked to enhanced well-being, as reflected in increased work engagement, and reduced burnout. The results further showed that this association is mediated by nurses' perceptions of job resources and intrinsic motivation. Notably, while job demands mediated the relationship between EL and nurses' well-being, the relationship became unsignificant when including intrinsic motivation as second mediator. Conclusions: Engaging leaders foster a favourable work environment for nursing staff which is not only beneficial for their work motivation but also for their work-related well-being. Engaging leadership and job resources are modifiable aspects of healthcare organisations. Interventions aimed at developing engaging leadership behaviours among nursing leaders and building job resources will help healthcare organisations to create favourable working conditions for their nurses. Trial Registration: The study described herein is funded under the European Union's Horizon 2020 Research and Innovation programme from 2020 to 2023 (Grant Agreement 848031). The protocol of Magnet4Europe is registered in the ISRCTN registry (ISRCTN10196901). [ABSTRACT FROM AUTHOR]