Abstract: The migration process of leached uranium in the in-situ leaching of uranium is considered a typical reactive transport problem. During this process, the lixiviant concentration and injection rate are important in-situ leaching process parameters (ISLPP) to efficiently recover uranium. However, several uncertain factors affect the outcomes of the ISLPP design. In addition, the repeated use of the reactive transport model (RTM) for investigating the acid in-situ leaching of uranium with the application of the Monte Carlo method leads to a substantial computational load. For this reason, a machine learning (ML)–based surrogate model was developed with the backpropagation neural network (BPNN) method to replace the RTM under the condition of uncertain parameters. Moreover, the simulated annealing optimisation model for ISLPP was created based on the proposed surrogate model. The optimal ISLPP was achieved that generated maximum profits from uranium recovery under different lixiviant prices, uranium prices and exploitation times. The optimal design framework of ISLPP based on the proposed ML algorithm was then applied in the Bayan-Uul sandstone-type uranium deposit in Inner Mongolia, China. From our analysis, it was demonstrated that the ML-based surrogate model exhibited great fitness with the RTM. The optimal results of the ISLPP indicated that the lixiviant concentration and injection rate could be adjusted based on the fluctuations in lixiviant price, uranium price and exploitation time. If the prices of sulphuric acid were high, a specific concentration of hydrogen peroxide could be injected into the injection well to promote the oxidation and dissolution of the uranium ore to increase the income from the uranium recovery. The optimisation model can also use the ISLPP scheme to boost the revenues from different lixiviant prices, uranium prices and exploitation times under the uncertainty of porosity, illustrating the applicability of the ML-based optimal design method of ISLPP in ISL mining. A general framework for developing surrogate models, as well as for conducting uncertainty analyses for a wide range of groundwater models was proposed here yielding valuable insights.