Abstract: With the increasing demand for urban flood control and drainage, the importance of large liquid storage structures is becoming more and more prominent. This study established a three-dimensional numerical analysis model of reinforced concrete large liquid storage structures considering highly nonlinear fluid-structure interaction effects based on computational fluid dynamics and the Lagrangian-Eulerian method (CFD-ALE). It focused on revealing the fluid spatial sloshing effect and failure mode of large liquid storage structures under seismic action, and studied the influence laws of liquid depth and support column spacing on the seismic response of the structure. The results show that under seismic action, the fluid pressure rises sharply and the spatial distribution is significantly different. The corners of the top and bottom slabs of the structure bear the maximum fluid pressure. The severe sloshing of the fluid will cause significant differences in the seismic response of various parts of the structure. Obvious high stress and strain concentrations will occur at the intersection of the side wall and the top slab, the corner of the side wall, and the intersection of the support column and the top slab. The concrete of the side wall and the top slab of the structure may be damaged due to excessive strain, and the bottom of the support column has excessive strain and is prone to shear failure. The liquid depth and support column spacing have a significant impact on the fluid pressure and liquid surface sloshing height. The deeper the liquid depth and the larger the support column spacing, the greater the peak strain of the support column and the peak strain of the wall and top slab.