Acid in situ leaching (ISL) is a common approach to the recovery of uranium in the subsurface. In acid ISL, there are numerous of chemical reactions among the injected sulfuric acid, groundwater, and porous media containing ore layers. A substantial amount of radioactive elements including U, Ra, Rn, as well as conventional elements like K, Na, and Ca, and trace elements such as As, Cd, and Pb, are released into the groundwater. Thus, in acid ISL, understanding the transport and reactions of these substances and managing pollution control is crucial. In this study, a three-dimensional reactive transport modeling (RTM) using TOUGHREACT was built to investigate the dynamic reactive migration process of UO22+, H+, and SO42− at a typical uranium mine of Bayan-Uul. The model considering the partial penetration through wellbore in confined aquifer and complex chemical reactions among main minerals like uranium, K-feldspar, calcite, dolomite, anhydrite, gypsum, iron minerals, clay minerals, and other secondary minerals. The results show that after mining for one year, from the injection well to the extraction well, the spatial distribution of uranium volume fraction does not consistently increase or decrease, but it decreases initially and then increases. After mining for one year, the concentration front of UO22+ is about 20 m outside the mining area, the high concentration zone is mainly inside the mining area. The concentration front of H+ is no more than 50 m. SO42− is the index with the highest concentration among the three indexes, the concentration front of SO42− is no more than 100 m. The concentration breakthrough curve of the observation well 10 m from the mining area indicates that the concentrations of the three indicators began to significantly rise approximately after mining 0.05 years, reached the maximum value after mining 0.08 to 0.1 years, and then stabilized. The parameter sensitivity of absolute permeability and specific surface area of minerals shows that the concentration of H+ and SO42− is positively correlated with absolute permeability. The concentration of H+ is negatively correlated with the specific surface area of calcite, anhydrite, K-feldspar, gypsum, hematite, and dolomite. The concentration of SO42− is positively correlated with the specific surface area of K-feldspar and Hematite, and negatively correlated with the specific surface area of calcite, anhydrite, gypsum, and dolomite. The influence analysis of pumping ratio and non-uniform injection ratio shows that the non-uniform injection scheme has a more significant impact on pollution control. The water table, streamline, capture envelope, and the concentration breakthrough curve of five schemes with different pumping ratios and non-uniform injection ratio were obtained. The water table characteristics of five schemes shown that increase in the pumping ratio and the non-uniform injection ratio, the water table convex near the outer injection well is weakened and the groundwater depression cone near the pumping well is strengthened. This characteristic of water table exerts a notable retarding influence on the migration of pollutants from the mining area to the outside. For the scheme with a pumping ratio is 0 (the total pumping flow rate is equal to the total injection flow rate) and a non-uniform injection ratio is 0 (the flow rate of inner injection well Q1,Q2,Q3 is equal to the flow rate of outer injection well Q4,Q5,Q6), the streamline characteristics shown that a segment of the streamline of is diverging from inner region to the outer region. For other schemes, the streamline exhibits a convergent feature. It is indicated that by increasing the pumping ratio and non-uniform injection ratio, a closure flow field can be established, confining the groundwater pollutants resulting from mining within the capture envelope. Hence, the best scheme for preventing pollution migration is the scheme with a pumping ratio is 0 (the total pumping flow rate is equal to the total injection flow rate) and a non-uniform injection ratio is 0.1 (the flow rate of inner injection well Q1,Q2,Q3 is 10% more than the flow rate of outer injection well Q4,Q5,Q6). In this scheme, the optimal stable concentration of UO22+, H+, and SO42− at the observation well obtained by RTM is lower than other schemes, and the values are 0.00316 mol/kg, 2.792 (pH), and 0.0952 mol/kg. The inner well injection rate is 194.09 m3/d, the outer well injection rate is 158.89 m3/d, and the pumping rate is 264.00 m3/d. Numerical simulation analysis suggests that a scheme with a larger non-uniform injection ratio is more conducive to the formation of a strong hydraulic capture zone, thereby controlling the migration of pollutants in the acid ISL. A reasonable suggestion is to adopt non-uniform injection mining mode in acid ISL.