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As a consequence of seasonal variations in groundwater level and reservoir water level, natural rocks generally experience the cyclic wetting-drying process, in which the change in microstructure becomes a critical factor leading to the deterioration of the macro-physical and mechanical properties of rocks. However, it remains a great challenge to quantitatively characterize the microstructures of rock, especially during the wetting-drying process. In this study, a systematic experimental investigation involving multiple techniques (mercury injection capillary pressure (MICP), computer tomography (CT), scanning electron microscope (SEM), and pores (particles) and cracks analysis system (PCAS) software package-based image analysis) were conducted to study the microstructure of sandstone subjected to cyclic wetting-drying. The results show that sandstone experiences increasing microporosity during the cyclic wetting-drying process, with progressive changes in micro grains, defects, and micropore structure and morphology. The pore compositions gradually change into a bimodal distribution with dominating small-medium pores (10 nm-10 μm) and large pores (>10 μm). Eventually, connected crack networks and large-scale fractures develop. There is a strong correlation between the microporosity values evaluated by CT and MICP, indicating the capacity of describing the micropore compositions ranging from 0.03 to 0.78 mm. Besides, comparisons of the three techniques (i.e., MICP, CT, and SEM) and evolution mechanisms of sandstone microstructures are further discussed. • Sandstone microstructures under cyclic wetting-drying are studied via multiple techniques. • Pore area, complexity, and microporosity gradually increase, and defects grow. • Micropores have a bimodal distribution with small-medium pores and large pores being dominant. • Micropores show morphological anisotropy in three dimensions. • CT agrees with MICP in describing micropore compositions ranging from 0.02 to 1 mm. [ABSTRACT FROM AUTHOR]