Compared to the general layered sites, the seismic resistance and mitigation of underground structures in site with weak interlayer are more prominent. This paper takes the double-story and double-span rectangular frame subway station structure as the research object. Based on the finite element software ABAQUS, a static and dynamic finite element analysis model of the soil-structure system is established. The influence of weak interlayer on the seismic response law of the subway station structure is studied, and the seismic mitigation effect of the station structure with friction pendulum bearings in homogeneous and weak interlayer sites is compared and analyzed. The results show that when the weak interlayer passes through the structure of a subway station, a notable increase in overall deformation, central column deformation, and internal forces at the base of the central column is brought about. Moreover, as the thickness of the interlayer increases, the increase in structural deformation and internal force becomes more significant. The installation of friction pendulum bearings at the top of the central column reduces the maximum displacement and internal force values of the central column, and the seismic mitigation effect of the friction pendulum bearings in sites with weak interlayer is significantly better than that in general homogeneous sites. The friction pendulum bearings are recommended to be used for seismic mitigation design in underground structures in sites with weak interlayer.