Water leakage is one of the most severe problems when the reservoir is constructed in the karst stratum due to the existence of complex geo-structural karst zones. A cascade approach was conducted during the construction of an anti-leakage project for a reservoir in Yunnan province, China, to investigate the subsurface karst system along with an anti-leakage curtain for grouting. The approach involved cascade geophysical investigation and geological interpretation, i.e., integration of data acquired using different methods, including surface electrical resistivity tomography (S-ERT), seismic reflection tomography, geological drilling, and three-dimensional (3D) cross-hole electrical resistivity tomography (CHERT). Geological drilling plans were prepared based on the tomography results. Data obtained from the drilling, in turn, were employed to confirm and calibrate the tomography results. The relationship among the geology, lithological characteristics, and geophysical properties of the region was established by analyzing the results of surface geophysical methods and geological drilling. A statistical relation was then used to transform the 3D cross-hole electrical resistivity tomography results into geological results. The results revealed the 3D spatial distribution and connectivity of the complex karst system in the anti-leakage curtain grouting areas of the reservoir. Based on the characterization, geometry, spatial distribution, and geological conditions of the karst zones, the potential leakage points and leakage paths were identified. The results can be used as guidance for reservoir curtain grouting projects in devising preventive strategies for water leakage.