Under the new normal, the economic development mode and growth momentum of China has brought about fundamental changes, which means that the development of enterprises has gradually shifted from being factor-and investment-driven to being innovation-and talent-driven. As the foundation of corporate innovation, employee creativity plays an important role in this process. In the field of strategic human resource management, high-performance work system is the embodiment of its core competence. Although some research has begun to try to explore the impact of high-performance work system on employee creativity, the underlying mechanism and the boundary condition is not yet fully understood. According to the Job demands-resources (JD-R) model, this study theorized and examined whether and when high-performance work system stimulate employee creativity. Using a sample of large and medium-sized enterprises in China, we collected data, which are time-lagged and multilevel, from 266 employees in 61 departments. Results of the hierarchical linear model found that (1) High-performance work system is positively related to employee creativity; (2) High-performance work system positively affects employee work well-being; (3) Work well-being positively affects employee creativity; (4) Employee work well-being partially mediates the relationship between high-performance work system and creativity; (5) Transformational leadership, which represents an important contextual variable in the workplace, moderates the relationship between work well-being and employee creativity; (6) Moreover, we have also revealed that transformational leadership can moderate the indirect effect of high-performance work system on employee creativity. We discussed the theoretical and practical implications of these findings.