This study investigated the sealing performance of the multistage liquid-sealing impellers of a turbopump. To achieve this purpose, the influence of each structural parameter in the impeller on the pressurization coefficient φ2 and the leakage flow rate Q was analyzed based on response surface methodology, taking the maximum pressurization coefficient φ2 and the minimum leakage flow rate Q as the optimization objectives. We obtained satisfactory ranges for parameters φ2 and Q. A set of parameter combinations was selected as the optimization scheme using the Box–Behnken method for the optimal solution design. The numerical simulation results show that to keep φ2 and Q in the better range, the value ranges of groove width b, groove depth h and groove number z should be (12.8–14 mm), (4.5–5.6 mm) and (23.5–28), respectively. Compared with the original model, the optimized version has an average increase of about 2.5% in pressurization coefficient φ2 at each rotation speed, an average of about 8.2% reduction in the leakage flow rate Q in the leakage state and an average increase in the reverse flow rate Q by about 6.7% in the negative pressure sealing state, indicating better sealing. By comparing pressure data at the experimental monitoring points, the proposed method was verified to have a high degree of confidence.