Gansu clay-sulfate rock is a special red-bed rock that formed in an evaporation environment with strong oxidation. Due to the high content of hydrophilic minerals (including clay mineral, sulfate, and carbonate), tunnel in clay-sulfate rock stratum has a potential risk of large expansive deformation after the erosion of groundwater. In this study, a loadable cyclic drying-wetting instrument was designed to simulate the occurrence of the surrounding rock mass of a tunnel experiencing a periodic change in groundwater level. Firstly, a series of drying-wetting cycle tests with different normal pressure were carried on to obtain the expansion regulation of clay-sulfate rock. Then, computed tomography (CT) and scanning electron microscope (SEM) tests were carried on to explain the corresponding mechanism in mesoscopic. The test results show that large expansive deformation was generated in the first water immersion and only part of the deformation can be recovered during the later drying process. During the 2–5 cycles, expansion-shrink deformation is much less than in the first cycle, and the volume of the sample tends to be constant. Meanwhile, the degeneration of the clay-sulfate rock was observed in the first cycle by the CT and SEM test. Then the mesostructure of the sample is stable during the 2–5 cycle. It indicates the clay rock, in large part, degenerated to clay soil during the first drying-wetting cycle. Structural degradation and hydration of anhydrite is the main source of irreversible expansive deformation. Moreover, normal stress and confined restraint can reduce or even eliminate the expansive deformation, however, cannot avoid the degeneration of mesostructure. The shear strength of Gansu clay-sulfate rock also decreased after the first drying-wetting cycle, which manifested as the attenuation in both cohesion and internal friction angle.