Whether the diaphragm wall should be considered in the seismic design of the column-free large-span subway station has not been uniformly determined. Based on the finite element numerical analysis software ABAQUS, the soil-structure static and dynamic coupling finite element models are established to analyze the influence of diaphragm wall on the seismic response of column-free large-span subway station under horizontal and vertical earthquake load. The results show that the diaphragm wall can improve the lateral stiffness of the column-free large-span subway station system, and the horizontal relative deformation of the side wall is reduced when the diaphragm wall is considered. However, the existence of diaphragm wall will magnify the vertical inertia effect of the overlying soil of the subway station, and also make the internal force of the subway station redistribute. When the diaphragm wall is considered, the end of the bottom slab is a weak seismic link, which should be properly strengthened in the seismic design.