Aiming at the water quality characteristics of low uranium concentration, high sulfate and high suspended solids in the seepage water of a decommissioned uranium mine in southern China, as well as the problems of unstable treatment effect, easy saturation and hardening of resin, and high operation and maintenance costs in the original resin adsorption uranium removal process, combined with the seasonal dynamic change law of uranium occurrence state under the background of the mine's karst landform, the analysis of seepage water quality characteristics and the optimization of treatment process were carried out. On the basis of finding out the cyclic mode of uranium "activation and migration in rainy season, local enrichment in dry season" and the difference of occurrence states in winter and summer, a seasonal combined treatment scheme of iron-based permeable reactive barrier (PRB) was proposed, and the process flow design, engineering facility planning and seasonal process parameter optimization were completed. The designed treatment capacity of the project is 400 m³/d, which can adapt to the seasonal fluctuation characteristics of the seepage water volume and uranium occurrence form of the mine, with an expected operation cycle of 10 years, and the materials can be recycled after regeneration. The application results show that the process has a significant removal efficiency for radioactive pollutants such as natural uranium, ²²⁶Ra, ²¹⁰Pb and ²¹⁰Po, the effluent water quality meets the standard stably for a long time, which can provide technical reference and engineering demonstration for the seepage water treatment of similar decommissioned uranium mines in karst areas.