Buildings of more than 34,000,000m2 areas are heated by hydro-geothermal energy in Tianjin, China. Karst reservoir is currently the most important hydro-geothermal resources under utilization. However, the imbalance between production and injection leads to a sharp decline of geothermal pressure. Thus, the geothermal doublet system composed of injection and production wells is required for sustainable production. This study takes Panzhuang karst geothermal reservoir (PGR) as an example, and establishes a regional-scale 3D realistic geothermal model to understand the natural status of temperature distribution in PGR, and the variation of temperatures in both production reservoirs, caprocks and deep wells under exploitation. Furthermore, the well placement is optimized, considering economic cost, to maintain the reservoir pressure and reduce the risk of heat breakthrough. The results show that the injection well should be placed downstream to the production well with a distance of 700 m. The optimized production and injection rates are estimated at 150 m3/h, which is able to maintain the wellhead temperature with the range from 97.5 °C to 99.5 °C, heat extraction rate of 12.4 MW for 50 years and the maximum pressure change in the reservoir below 140 kPa.