The process parameters in the low-pressure casting of large-size aluminum alloy wheels are systematically optimized in this work using numerical casting simulation, response surface methodology (RSM), and genetic algorithm (NSGA-II). A nonlinear input–output relationship was established based on the Box–Behnken experimental design (BBD) for the crucial casting parameters (pouring temperature, mold temperature, holding pressure, holding time), and response indicators (defect volume fraction, spokes large plane mean secondary dendrite spacing (SDAS)), and a mathematical model was developed by regression analysis. The Isight 2017 Design Gateway and NSGA-II algorithm were used to increase the population and look for the best overall solution for the casting parameters. The significance and predictive power of the model were assessed using ANOVA. Casting numerical simulation was used to confirm the best option. To accomplish systematic optimization in its low-pressure casting process, the mold cooling process parameters were adjusted following the local solidification rate. The results showed that the mathematical model was reliable. The optimal solutions were a pouring temperature of 703 °C, mold temperature of 409 °C, holding pressure of 1086 mb, and holding time of 249 s. The mold cooling process was further optimized, and the sequence solidification of the optimal solution was realized under the optimized cooling process. Finally, the wheel hub was manufactured on a trial basis. The X-ray detection, mechanical property analysis, and metallographic observation showed that the wheel hub had no X-ray defects and its mechanical properties were well strengthened. The effectiveness of the system optimization process scheme was verified.