Simulation and experimental studies were performed on filling imbalance in geometrically balanced injection molds. An original strategy for problem solving was developed to optimize the imbalance phenomenon. The phenomenon was studied both by simulation and experimentation using several different runner systems at various thermo-rheological material parameters and process operating conditions. Three optimization procedures were applied, Response Surface Methodology (RSM), Taguchi method, and Artificial Neural Networks (ANN). Operating process parameters: the injection rate, melt temperature, and mold temperature, as well as the geometry of the runner system were optimized. The imbalance of mold filling as well as the process parameters: the injection pressure, injection time, and molding temperature were optimization criteria. It was concluded that all the optimization procedures improved filling imbalance. However, the Artificial Neural Networks approach seems to be the most efficient optimization procedure, and the Brain Construction Algorithm (BSM) is proposed for problem solving of the imbalance phenomenon.