Groundwater heat pump (GWHP) system directly uses a stable temperature of groundwater for cooling and heating of buildings or districts. In this study, a simulation-optimization model for the sustainable operation of GWHP system was developed. The simulation model computed the coupled groundwater flow and heat transport with considering thermal recycling. As an optimization technique, genetic algorithm was linked with the simulation model. The developed model can determine the optimal extraction and injection rates of GWHP system to maximize system performance and efficiency, to maintain stable operation, and to minimize costs and environmental impacts. Assuming a 2D hypothetical aquifer, it was demonstrated how the optimal operation of GWHP system obtained from the model can be changed according to several operational and hydrogeological conditions, including well distance, regulation on injection water temperature, hydraulic conductivity, and regional hydraulic gradient. The results highlighted a necessity to determine an operational strategy of GWHP system through the optimization able to consider site-specific condition. In addition, the performance and capability of the developed model were demonstrated by obtaining the optimal strategy for the cooling operation of a research-oriented GWHP facility installed in Korea.