Doublet well system composed by extraction and injection wells is widely used for heat production from deep geothermal reservoirs. The large-scale implementation of doublet well systems lead to hydro-thermal interaction with the natural hydro-thermal flow system; this affects heat production efficiency and sustainable management of geothermal energy and groundwater resources. However, the interaction between artificial operations and nature hydro-thermal status was seldom considered in the well placement optimization. In this study, the natural status of hydro-thermal flow was determined by fitting numerical modeling output to the groundwater level and temperature observations, in a realistic site of the Gonghe Basin, China. The well separation and relative position were then optimized against background water flow direction. It was found that a well separation of 1200 m with the injection well located upstream (south) to the extraction well can maximize the volume of injected water entering extraction well, without influence on the outflow temperature. Based on this finding, we further compared the effects of “extensive well placement” where the wells were located sparsely in entire geothermal field, and “intensive well placement” where the wells were located centrally in a local region. The calculation showed that the performance of intensive well placement was superior to extensive well placement with higher outflow temperature and lower interruption in groundwater levels. Further optimization of intensive well placement resulted in the outflow temperature higher than 92 ^°C under the total outflow rate of 30,000 m³/d for 30 years, and the groundwater level changes can be controlled below 6.0 m. The multiple-step well placement optimization approach and novel intensive heat production mode regarding nature status of hydro-thermal flow in geothermal reservoirs, provides important reference to the other geothermal field for large-scale geothermal exploitation.