Natural rock and soil masses generally suffer from weathering of cyclic wetting-drying due to groundwater variation, reservoir level fluctuation, and evaporation, etc. Thoroughly understanding this deterioration mechanism requires the investigation of the physical and mechanical properties of rock and soil masses from a multi-scale view. In this study, sandstone from the interbedded weak and hard strata in Zigui Basin, China, where hundreds of landslides were distributed, was used to study the multi-scale deterioration mechanism of cyclic wetting-drying of Yangtze River water on it. Comprehensive laboratory experiments regarding microstructural, physical, and mechanical properties of sandstone samples were conducted. With the probabilistic characteristics of the geological strength index of sandstone estimated through a modified Bayesian sequential updating method, probabilistic characteristics of geotechnical properties of sandstone rock mass were then evaluated based on the generalized Hoek-Brown criterion. The results indicated that the geotechnical properties of sandstone samples changed significantly under the effect of cyclic wetting-drying, then tended to be stable after a long-term effect. The used river water showed a distinctive deterioration effect compared to distilled water and ionized water having similar ion compositions with the river water, due to the chemical interactions and possible microorganism effects. Besides, the mechanical strength of sandstone rock mass undergone cyclic wetting-drying showed similar variation trends with those of sandstone samples. Under cyclic wetting-drying, the mechanical strength and indices of Hoek-Brown criterion of sandstone rock mass followed normal distribution or skewed distribution. This study provides a scientific basis and technical reference for understanding the cyclic wetting-drying effect and water-rock interaction, and may further contribute to the research associated with geological hazards and engineering failure.