Under the action of the reservoir water level cycle, the physical and mechanical properties of the reservoir bank slope deteriorate, causing bank deformation and slippage, which will produce different degrees of damage to the bridge foundation, piers and superstructure, and even lead to the bridge superstructure falling and collapsing. Aiming at the problem of instability of the bank slope of a Yangtze River Bridge in the Three Gorges Reservoir area, a three-dimensional finite element model of bank slope and bridge was established by using the FEM-SPH conversion coupling algorithm. Combined with the geological conditions of the bridge location, the whole process of bank slope deformation, slippage and instability under changing water level conditions is simulated, the interaction mechanism between bank slope slippage and bridge pile foundation is revealed, and the deflection law of bridge piers and the failure mode of the substructure are studied. The results show that: Taking the sliding zone finite element meshes all converted into SPH particles as the bank slope instability criterion, the FEM-SPH conversion coupling algorithm can more intuitively and accurately simulate the whole process of the reservoir bank slope from deformation, slippage to instability. The bank slope at the bridge location will be destabilized during the 16th and 20th water level rise and fall cycles. With the evolution of bank deformation, slippage and instability, the bridge pier deflection shows a trend of "slowly increasing-surge". When the second instability occurs on the bank slope, the pile foundation undergoes shear failure at the upper part of the soil-rock interface, and the angle between the failure plane and the horizontal plane is about 60°.