Abstract: To study the combined mechanical characteristics of the ship lock chamber-pile foundation under asymmetric loads during the completion, operation, maintenance, and check conditions, a three-dimensional finite element numerical simulation was adopted based on the ship lock project in the lower reaches of the Ganjiang River to investigate the deformation and stress response of the structure. The results show that the overall settlement of the ship lock chamber structure is significant under the self-weight-dominated condition, with the maximum settlement occurring in the middle of the chamber bottom plate, reflecting the key role of load concentration and stiffness coordination in the central area. During the operation condition, obvious lateral displacement occurs at the top of the lock wall, indicating the significant impact of asymmetric loads on the lateral displacement of the water-retaining structure. Under the maintenance condition, the compressive stress concentration in the junction area of the lock chamber-pile foundation is prominent, and under the check condition, the tensile stress at the corner of the lock wall is relatively significant. This indicates that the structure transition and geometric mutation areas are stress-sensitive parts, and the piles in the areas with sudden changes in load and stiffness bear large forces. This study can provide a theoretical basis and engineering reference for the structural design of similar ship lock projects and the differential treatment of pile foundations.