Abstract: With rising demands for urban flood control and drainage measures, large liquid storage structures are becoming increasingly important. In this study, we established a three-dimensional numerical analysis model to investigate highly nonlinear fluid-structure interaction effects in large re-inforced concrete liquid storage structures on the basis of computational fluid dynamics and the Lagrangian-Eulerian method (CFD-ALE). We focused on revealing the fluid spatial sloshing effect and failure modes of large liquid storage structures under seismic activity and studied the effects of liquid depth and support column spacing on the seismic response of the structure. The model showed that under seismic activity, the fluid pressure increases sharply and the spatial distribution differs significantly. The corners of the top and bottom slabs of the structure bear the maximum fluid pressure. Severe fluid sloshing causes significant differences in the seismic responses of various parts of the structure. High stress and strain will occur at the intersection of the side wall and top slab, the corner of the side wall, and the intersection of the support column and top slab. The concrete of the side wall and top slab may be damaged by the excessive strain, and the bottom of the support column is also excessively strained and prone to shear failure. The liquid depth and support column spacing significantly affect the fluid pressure and liquid surface sloshing height. The greater the liquid depth and the larger the support column spacing are, the greater the peak strain in the support column, wall, and top slab will be.