Horizontal spiral-coil type ground heat exchanger (HSGHE) has been increasingly used in ground source heat pump systems owing to its high heat transfer performance and low cost. This study proposes a method to optimize the design and operation parameters based on the combination of response surface methodology (RSM) and multi-objective genetic algorithm (MOGA). First, a 3D numerical model simulating the thermal–hydraulic characteristics of the HSGHE was built and the reliability of the model was validated through an indoor test rig. Subsequently, some parametric studies were performed to analyze the degree of influences that each input parameter on the outputs. On this basis, the Box-Behnken design method and RSM were used to establish response surface models between the input parameters (spiral diameter, pitch, and fluid velocity) and objective functions (net heat exchange rate and thermal performance capability) and determined the interactions between them. The results showed that the spiral diameter had the most significant influence, followed by the pitch, and fluid velocity. Finally, based on the developed models, the MOGA employing the Pareto optimum solutions were used to optimize the design and operation parameters and determine their optimal combination: spiral diameter of 0.4 m, pitch of 0.1 m, and fluid velocity of 0.4 m/s. The findings of this study may assist designers in the development of high efficiency ground heat exchangers.