A constitutive model for damage is proposed to describe the deformation and strength characteristics of sandstone under the coupled effects of wetting-drying cycles and cyclic loading. First, the microparameters of sandstone were calibrated by wetting-drying cycles and uniaxial compression tests. Subsequently, a discrete element model of the specimen was established by numerical simulation software (PFC2D), and a cyclic loading test was performed to obtain relevant test data. Second, assuming the microdamage of the sample is described by the Weibull distribution, the macrodamage can be described by a mechanical model. Based on the Lemaitre strain equivalence hypothesis, the coupled damage variable of the specimens was derived. Finally, the constitutive model of damage of sandstone under the coupled effects of wetting-drying cycles and cyclic loading was derived from the statistical mechanics theory of damage. In addition, the damage evolution process of sandstone under the coupled effects of wetting-drying cycles and cyclic loading was validated by an analysis of the microscopic force field and calculations of the damage variable. Compared with the existing models, the constitutive model proposed in this paper can better reflect the stress-strain relationship and damage evolution of sandstone under the coupled effects of wetting-drying cycles and cyclic loading.