In order to study the influence of wetting-drying cycles on the mechanical parameters of metamorphic sandstone, the deteriorating characteristics and mechanism of major rock mechanical parameters in the process of wetting-drying cycles were studied by laboratory test. The results demonstrate that the number of cycles is negatively correlated with the changes of uniaxial compressive strength, elastic modulus, tensile strength, cohesion and internal friction angle, but positively correlated with the changes of Poisson’s ratio; in the initial stage of the cycles, the change rate of each mechanical parameter is fast, but it stabilizes with the increase of the cycles. According to the analysis of the deteriorating degree D after 28 cycles, the sensitivity degree of wetting-drying cycles to various mechanical parameters is as follows: Poisson’s ratio>tensile strength>cohesion>elastic modulus>internal friction angle>compressive strength. The analysis of rock microstructure changes in the process of the wetting-drying cycles show that the main causes of rock mechanical damage in this experiment are the dissolution dissipation of easily hydrolyzed minerals, the expansion of dissolution fissures and the shedding of dissolution debris particles. The regression model of mechanical parameters that change with the number of cycles was established, and its reliability was verified. Based on the test results and model analysis, it is believed that the rock mechanical parameters tend to stabilize after 16 cycles, so this number of cycles is recommended for the selection of mechanical parameters in engineering design.