This study aimed at improving the residual wall thickness uniformity (RWTU), which was closely related to the mechanical properties of plastic parts with a hollow cross-section, in short-fiber reinforced composites (SFRC) overflow water-assisted injection molding (OWAIM). The influences of five independent process parameters (melt temperature, mold temperature, delay time, water pressure, and water temperature) on RWTU were investigated through the methods such as central composite design, regression equation, and analyses of variance. Response surface methodology (RSM) and artificial neural network (ANN) optimized by genetic algorithm (GA) were employed to map the relationship between the process parameters and the standard deviation (SD) depicting the RWTU. Comparison assessments of three models (RSM, ANN, and ANN-GA) were carried out through some statistical indexes. It was concluded that the effect of melt temperature, delay time, and water temperature were significant to RWTU; the hybrid ANN-GA model had the best performance for predicting SD compared with RSM and ANN; the least SD obtained in optimization using ANN-GA as a fitness function was 0.0972.