In situ leaching (ISL) is the main mining method for sandstone-type uranium deposits. The thermodynamic model can provide important information to real project decision making. However, systematic thermodynamic modeling work is still lacking for uranium-containing systems. In this paper, a thermodynamic model for the uranium minerals-solution-gas system is established with reliable and internal consistent parameters. The B-dot model and Peng-Robinson model are used to calculate the activity coefficients and fugacity coefficients. The determination for the equilibrium constant is carried out based on the comparisons between the calculated results by this model and the experimental solubility data. The solubility of uranium minerals under different experimental conditions can be reproduced by this model. 12 Tetravalent uranium minerals are less soluble than hexavalent uranium minerals in the absence of oxidants, especially under alkaline conditions. The dissolution of uranium mineral assemblages, including pitchblende, uraninite, coffinite, and brannerite, will be promoted by reducing the temperature or increasing the concentration of the leaching or oxidizing agents. For uranium leaching, the efficiency of the acid method is higher than that of the alkaline method, which probably results from the transformation of soluble uranium minerals into insoluble uranium minerals with less solubility in alkaline solutions. Under the CO2 + O-2 leaching condition, the dissolution of uranium minerals will be promoted by increasing the partial pressure of O-2 or CO2, and dissolution is more sensitive to O-2 at high pressure. In addition, two real ISL projects from China have been calculated using the model. The suitable ratio of water and solids and the concentrations of both the oxidant and the leaching agent are suggested for these two projects.