The lithology and composition type of an aquifuge in overburden play a crucial role in influencing the crack evolution and permeability changes of the aquifuge. This study utilized the high-temperature and high-pressure rock triaxial seepage test system to conduct triaxial compression tests on mudstone, sandstone, and their combined rock samples. The mechanical characteristics and permeability evolution of each lithology law during the failure were investigated. Furthermore, computed tomography (CT) scanning technology was utilized for the three-dimensional (3D) reconstruction and theoretical permeability calculation of single and combined rock samples. The results indicated that the stress–strain curves for single and combined rock samples exhibited similar patterns, which were divided into four stages: pore compaction, linear elasticity, yield deformation, and post-peak residual deformation. The peak strength of rock samples positively correlated with confining pressure. Permeability trends for mudstone and sandstone exhibited an “N”-type pattern characterized by “slow decrease–gradual stabilization–sudden increase–rebound decrease”, while the permeability of mudstone–sandstone combined rock followed a “U”-type pattern of “initial decrease–stabilization–subsequent increase”. Notably, the permeability of the combined rock samples was significantly lower compared to the single rock samples. The failure mode indicated that fractures in a single rock sample transversed the entire sample, whereas failures in the combined rock samples were confined to the mudstone component. This observation accounted for the differences in the permeability changes between the rock sample types. Additionally, the theoretical permeability results from the 3D reconstruction correlated with the experimental results.