In order to explore the influence of the interaction between superstructure and substructure on the seismic response of ground plant of hydropower station and aiming at the simplified analysis method widely used in seismic research at present, four schemes were selected to compare and analyse the influence of the amplification effect of the substructure, the coupling of the superstructure and substructure, and the linear elasticity model for concrete materials of the substructure on the seismic response of hydropower station plant based on engineering examples. The results showed that the seismic response of the powerhouse structure will be smaller and deviate greatly without considering the amplification effect of the substructure or the coupling of the superstructure and substructure, which will not be conducive to the seismic design of the structure, so it should be considered in the seismic analysis. The seismic response of powerhouse structure is larger but closer to the true value without considering the plastic mechanical behavior of the concrete material of the substructure. Further comparison of the energy distribution and damage evolution process of the hydropower station plant structure showed that the plastic deformation energy, the damage energy of the superstructure, and the damage region reduced. The damage of the downstream wall was more serious, but the failure models of the structure were similar, both are damaged at the intersection part of superstructure and substructure. Therefore, it is considered that the simplified seismic analysis with this method can reflect the interaction between superstructure and substructure more accurately, and it is also conducive to the seismic safety of ground plant of hydropower station.