The purpose of this paper is to examine the effect of High-Performance Work Practices (HPWPs) viewed from two sides of the Job Demands-Resources (JD-R) model on employee health. The proposed model was tested on 402 civil servants of the Indonesian Research and Innovation Agency. We utilized Partial Least Squares Structural Equation Modeling (PLS-SEM) to analyze the study. Our results show that HPWPs has a significant positive impact on employee health, job satisfaction, employee engagement, and challenge stressors. Besides that, we found that HPWPs has a negative impact on stressors and emotional exhaustion. In addition, job satisfaction, employee engagement, challenge and hindrance stressors become partial mediators in the positive effect of HPWPs on employee health. Meanwhile, supportive leadership tends to reduce the positive influence of HPWPs on employee health. The results of this study indicate that agencies should pay more attention to the dose of JD-R and the role of leadership in HPWPs in order to improve employee well-being. Because if job demands higher than the work resources, it has a negative impact on employees, even excessive leadership roles in the HPWPs have a negative impact on employees