Mudstones in the drawdown area are prone to disintegration under cyclic wetting-drying conditions during reservoir operation, which is unfavorable for bank slope stability. To study the influence of cyclic wetting-drying conditions on disintegration characteristics, disintegration tests with 11 wetting-drying cycles are conducted on mudstones from the Three Gorges Reservoir area. Experimental results show that in the first five wetting-drying cycles the disintegrated mass increases rapidly, while micropores, fractures, and flaky aggregates distributed on the surface generally develop, but afterwards the disintegrated mass changes slightly and the surface tends to be smooth. Then, a mathematical model based on the proposed disintegration index is established to quantitatively evaluate mudstone’s disintegration characteristic. The disintegration index generally decreases obviously in the first five wetting-drying cycles and approaches to 0 with little fluctuation after then. After 11 wetting-drying cycles, disintegration of the tested mudstone nearly tends to stop and does few adverse effects on bank slope stability.