Since the Fukushima nuclear incident in 2011, the focus on nuclear safety has intensified significantly, leading to heightened demands for nuclear power plant modeling to go beyond the mere dynamic analysis of soil–structure interaction (SSI) or fluid–structure interaction (FSI). In current engineering practice, FSI is typically described using simplified forms, such as loads or added mass. However, this approach lacks a comprehensive analytical framework that integrates refined FSI analysis with soil–structure interaction (SSI). This study analyzes the dynamic response of the nuclear island structural system using a fully coupled fluid–structure–soil interaction (FSSI) model. The effectiveness and validity of the model are verified through case comparisons. Simulations were conducted using the parameters of five different types of nuclear power engineering sites for both homogeneous and layered foundations. The results indicated that the hydrodynamic pressure response and acceleration amplification of layered foundations significantly exceeded those of homogeneous foundations, underscoring the importance of considering layered sites in the comprehensive complex modeling of nuclear power projects.