Abstract: Low-frequency vibrations can effectively improve natural sandstone permeability, and higher vibration frequency is associated with larger permeability. However, the optimum permeability and permeability evolution mechanism for uranium leaching and the relationship between permeability and the change of chemical reactive rate affecting uranium leaching have not been determined. To solve the above problems, in this study, identical homogeneous sandstone samples were selected to simulate low-permeability sandstone; a permeability evolution model considering the combined action of vibration stress, pore water pressure, water flow impact force, and chemical erosion was established; and vibration leaching experiments were performed to test the model accuracy. Both the permeability and chemical reactions were found to simultaneously restrict U6+ leaching, and the vibration treatment increased the permeability, causing the U6+ leaching reaction to no longer be diffusion-constrained but to be primarily controlled by the reaction rate. Changes of the model calculation parameters were further analyzed to determine the permeability evolution mechanism under the influence of vibration and chemical erosion, to prove the correctness of the mechanism according to the experimental results, and to develop a new method for determining the optimum permeability in uranium leaching. The uranium leaching was found to primarily follow a process consisting of (1) a permeability control stage, (2) achieving the optimum permeability, (3) a chemical reactive rate control stage, and (4) a channel flow stage. The resolution of these problems is of great significance for facilitating the application and promotion of low-frequency vibration in the CO2 + O2 leaching process.