Supercritical CO2 (sCO(2)) has been proven to be a promising working fluid for geothermal heat mining, and the produced hot sCO(2) can be directly used for power generation. However, the sCO(2) produced from a brine-based reservoir may contain a certain amount of water, preventing direct power-cycle utilization. In this paper, an axial vane separator was designed to address the separation problem of sCO(2) and water produced from geothermal reservoirs. First, the influences of operational and structural parameters on the separation performance were analyzed through numerical simulations. Five factors were selected to develop separation performance regression models by the response-surface method (RSM). Finally, geometrical parameter optimization was applied to these RSM models. The results show that the guide vane area and the exhaust inlet are the main locations impacting the system pressure drop. The separation performance can be affected by many factors, including the guide blade outlet angle, number of vanes, hub diameter, length of the vortex tube, droplet size, and inlet velocity. The water-droplet size and the number of vanes are the most critical factors affecting the separation efficiency. The inlet velocity, the number of vanes, and the hub diameter have a larger influence on the pressure drop of the separator. The optimization results indicate that the separation efficiency can reach 100% under certain operating conditions with a pressure drop no greater than 100 kPa.