Abstract: A dynamic centrifugal model test is designed and implemented for the soft clay—pile group foundation system. Two sets of prefabricated piles with different vertical loads are arranged, and the acceleration of the soft clay layer, lateral displacement of the bearing platform, and bending moment of the pile under natural seismic action are obtained under 50g gravity acceleration environment. Thus, the vertical deformation of the piles, relative displacement of the piles and soil, and soil resistance around the piles are derived and calculated. The influences and mechanisms of vertical loads on the seismic response of soft clay—pile group foundation system are analyzed and studied. The results indicate that: (1) The results of the response of bending moment of the piles under seismic action are complicated. When the unique zero point of bending moment of the piles occurs along the depth direction, the bending moment of the piles exhibits a decreasing tendency, then increases and decreases with the increase of the buried depth, and the probability of this case increases by 7.58% with the increase of the loads at pile top. (2) The loads at pile top have a certain effect on the bending moment of the piles, and the maximum of the bending moment of the piles decreases by 7% and the resisting force of the soils around the piles increases by 25.32% with the increase of the loads at pile top. (3) When the soft clay soil undergoes seismic subsidence, the relative displacement of the soils plays a dominant role in the pile—soil interaction, and the maximum values of the resistance and bending moment of the soils around the piles both appear near the maximum value of the relative displacement of the soils.