Red-bed mudstone is widely distributed throughout the Three Gorges Reservoir Area, China. This geological material easily disintegrates into fragments during engineering activities. The potential factors that influence the disintegration (grain composition, slake durability index, grain roundness, fractal dimension, and surface energy) and shear strength (cohesion and friction angle) of red-bed mudstone fragments are investigated via cyclic wetting and drying tests and direct shear tests. The results show that the disintegration process includes three stages and that the grains gradually become well graded. The roundness exhibits a linear relationship with the number of cycles. However, the variations in the slake durability index, fractal dimension (mass-size distribution based), surface energy, cohesion, and friction angle show three distinct stages. In addition, the fractal dimension (quantity-size distribution based) and friction angle are significantly affected by the assumption that the specimens are isotropic, and the grain behaviors involve compaction, rotation, and separation. The cohesion and friction angle display linear relationships with the slake durability index, roundness, fractal dimension (mass-size distribution based), and surface energy, indicating the potential to assess the shear strength of mudstone fragments from the aspect of disintegration.