Residual wall thickness is an important indicator for water-assisted injection molding (WAIM) parts, especially the maximization of hollowed core ratio and minimization of wall thickness difference which are significant optimization objectives. Residual wall thickness was calculated by the computational fluid dynamics (CFD) method. The response surface methodology (RSM) model, radial basis function (RBF) neural network, and Kriging model were employed to map the relationship between process parameters and hollowed core ratio, and wall thickness difference. Based on the comparison assessments of the three surrogate models, multiobjective optimization of hollowed core ratio and wall thickness difference for cooling water pipe by integrating design of experiment (DOE) of optimized Latin hypercubes (Opt LHS), RBF neural network, and particle swarm optimization (PSO) algorithm was studied. The research results showed that short shot size, water pressure, and melt temperature were the most important process parameters affecting hollowed core ratio, while the effects of delay time and mold temperature were little. By the confirmation experiments for the best solution resulted from the Pareto frontier, the relative errors of hollowed core ratio and wall thickness are 2.2% and 3.0%, respectively. It demonstrated that the proposed hybrid optimization methodology could increase hollowed core ratio and decrease wall thickness difference during the WAIM process.