The main difficulty in understanding the effects of chemical-physical composite stimulation for low-permeability sandstone-type uranium deposits is clarifying the influence of acidification on pore response mechanism and permeability-mechanical properties evolution during loading-deformation-failure process. Therefore, the acid-rock reaction experiment was first performed, the multiple testing methods (X-ray Diffraction, thin-section identification, high-pressure mercury intrusion porosimetry, stress-seepage coupling experiment) were then conducted, the evolution laws and mechanisms of reservoir physical characteristics after acidification were finally clarified. Results show that after the acid-rock reaction, the contents of calcite, feldspar and kaolinite of samples are decreased and the quartz content is increased, the permeabilities of samples are all promoted, the peak strength, elastic modulus, and shear modulus of samples are reduced and the Poisson’s ratio is raised. The acid-rock reaction changes the energy storage performance and promotes the plasticization of samples. It is suggested to adopt a lower sulfuric acid concentration (2 g/L) and longer reaction time (>45 d) for the ISL of uranium deposits. This work has important theoretical and practical significance for an in-depth understanding of the enhanced mining of low-permeability sandstone-type uranium deposits.