This study focuses on soil from the Three Gorges Reservoir area, simulates the changes in soil under different water pressures and varying numbers of wetting-drying cycles, investigates the response of soil aggregate size distribution and stability indices to high-pressure flooding and wetting-drying alternation, as well as the impacts of soil aggregate structural change on the migration and retention of sulfamethoxazole (SMX). Results demonstrated that water pressure and wetting-drying cycles affected both mechanical and water stability of soil aggregates. After one wetting-drying cycle under 100 kPa water pressure, the content of mechanically stable and water-stable aggregates larger than 5 mm increased by 49.46% and 31.79%, respectively, while the mean weight diameter (MWD) increased by 12.11% and 25.71%, respectively. In contrast, the application of 300 kPa water pressure reduced soil stability, with the MWD of water-stable aggregates decreased by 10.48% compared to the control group, and the aggregate breakdown rate (PAD) increased by 3.36%. After three wetting-drying cycles, the mechanical and water stability of the soil decreased with increasing water pressure and more frequent wetting-drying cycles. SMX exhibited strong migration ability in the tested soil, which was negatively correlated with soil stability indices, including MWD, geometric mean diameter (GMD), and the mass percentage of aggregates larger than 0.25 mm (R_0.25). The retention amount of SMX from high to low in soil aggregates with different sizes was in the order of 0.5-2 mm aggregates, >5 mm aggregates, >0.25 mm aggregates.