Bank slope stability has become a great concern, while the impoundment of Three Gorges reservoir. The bank slope composed of red-layer soft rock has exhibited distinct deformation and failure. Therefore, a typical red-layer soft rock around Three Gorges reservoir area was selected to demonstrate the process of cyclic changes at the reservoir level and immersion-air-dry cyclic action of water-rock inside hydro-fluctuation belt. To meet the objective of this study, a series of creep tests were conducted on the rock specimens at different water-rock interaction stages. The following points were noticed based on the laboratory results: (1) the creep fracture strength and long-term strength of red-layer soft rock degraded significantly during the process of water-rock interaction. For the first three water-rock interaction circulations, the strength of red-layer soft rock degraded quickly and then gradually became stable. (2) During the creep test, the lateral expansion of red-layer soft rock increased significantly regarding to the number of cycles. (3) The creep curve includes three typical stages at failure stress level—primary (damped) stage, secondary (steady-state) stage, and tertiary (nonlinear accelerated) stage. As the number of cycles increased, the percentage of secondary stage diminished gradually. However, the tertiary stage showed a gradual increment, since the plasticity of the specimens was strengthened by water-rock interaction. (4) The shear failure characteristics of the specimens became highly considerable during the process of water-rock interaction, and there have been a gradual increment of shear rupture zone. (5) The SEM results showed that the specimen microstructure changed its state from dense to loose and porous. The findings of this research provide a good basis for long-term stability analysis of bank slope.