The salts contained in water can gradually accumulate in pore networks of rocks under the cyclic wetting-drying process, which could cause rock deterioration. The salt-induced damage under wetting-drying cycles results in dynamically evolving mechanical and hydraulic properties of the rock, which is relevant to many rock-related engineering activities and geological disasters. In this study, the structure damage and permeability evolution of Three Gorges Reservoir (TGR) sandstone subjected to wetting-drying cycles with Na2SO4 solution were investigated by a series of multiscale experiments. The results showed that the salt solution has a great influence on the physical properties of TGR sandstone during the wetting-drying process. With the increase of wetting-drying cycles, two typical macroscopic damage modes in form of surface peeling and internal cracking were observed. Various parameters reflecting the internal structure of the TGR sandstone (i.e. pore size distribution, total porosity, effective porosity, and mass loss) indicated that the pore network was first blocked and then connected with increasing wetting-drying cycles. This variation of the pore network also profoundly affected the permeability of the TGR sandstone. Specifically, the permeability of the TGR sandstone initially decreased slightly due to the blocked seepage channels by salt crystallization, followed by slow growth with increasing wetting-drying cycles. The permeability of the TGR sandstone increased sharply at the cycle 15th because of the constant accumulation of damage on the internal structure. Functional relationships between the permeability and porosity as well as wetting-drying cycles were established. The deterioration mechanism of the TGR sandstone was further elucidated by an evaporation test in a tapered capillary tube. The evaporation test indicated that salt solution was more likely to crystallize in narrow pores and exerted pressure enough to crack the pores. The crystallization position and cracking pressure of salt solution contributed to the structure damage and permeability enhancement of TGR sandstone observed in this study. These results and findings deepen our understanding of salt-induced rock deterioration mechanism under the wetting-drying cycles and would be meaningful for rock engineering safety and geological disaster forecast in complex groundwater environments.