In order to compare and analyze the seismic response characteristics of a safety-related nuclear structure on a non-rock site in the condition of raft and pile group foundations under unidirectional and multidirectional seismic motion input, a large-scale shaking table test of the soil-nuclear structure system was carried out in this paper. In the test, the soil was uniform silted clay, and the shear wave velocity was 213 m/s. Considering the similarity of the superstructure natural frenquency, the actual nuclear power structure was simplified to a three-story frame shear wall structure model. The annular laminated shear model box was used to take the boundary effect of soil into consideration; the seismic motions = were input in only one horizontal direction or three directions at the same time for the shaking table test, and the results were analyzed. The results of the test show that the acceleration response of the safety-related nuclear plant is affected by the directions of input seismic motion and the forms of the foundation. When the seismic motion is input simultaneously in three directions, the acceleration responses of the horizontal motion and vertical rocking of the safety-related plant are larger than those of the single-direction input. The acceleration response of the horizontal motion and vertical rocking of the safety-related structure with the pile group foundation is smaller than that with the raft foundation. The values of most frequency bands in the horizontal acceleration Fourier amplitude spectrum at the top of the pile-foundation structure are smaller than that at the top of the raft-foundation structure, while the displacement is basically the same as that of the raft-foundation structure. This is related to the relation between the frequency component of input seismic motion and the natural frequency of the structure system. Therefore, it is more reasonable to use three-dimensional seismic input in the seismic response analysis of nuclear power plants. The seismic performance of nuclear power plants can be enhanced by using pile group foundations.