In the foreseeable future, the geothermal exploitation from hot dry rocks (HDR) using a horizontal well will bear potential. Thus, in-depth studies should be conducted on the selection of injection-production scheme (IPS) and working fluid, design of reinjection parameters, optimization of wellbore structure and materials, and analysis of geological settings. This paper proposed a fully coupled model to study the above scientific questions. For Model A, the working fluid was injected into the annulus and then flowed out of the thermal insulation pipe (TIP). Its temperature passes through two stages of temperature rise and two stages of temperature decline. But for model B, the working fluid was injected into the TIP and then flowed out of the annulus. Its temperature undergoes five stages, four stages of temperature rise and one stage of temperature decline. The results show that the Model A is the best IPS owing to its high outlet temperature, stable thermal recovery, and low fluid injection volume. In Model A, when the working fluid was supercritical carbon dioxide and the liquid injection volume was 135.73 m3/d, the heat recovery ratio (HRR) was as high as 85.40%, which was 17.85% higher than that of the Model B whose working medium was water, and its liquid injection volume was only 25% of that. Meanwhile, over ten years of continuous production, the outlet temperature decreased by 7.5 °C and 18.38 °C in the latter. The optimal working fluid has a low volume heat capacity and thermal conductivity for any IPS. Sensitivity studies showed that for the area that met the HDR standard, the effect of reinjection temperature on the outlet temperature can be ignored. As for Model A, HRR drops sharply by 6.74–9.32% when TIP goes from completely adiabatic to nonzero thermal conductivity. Meanwhile, the horizontal segment length of the TIP is shorter when Model A obtains the optimal outlet temperature compared with Model B. In addition, the correlation between the outlet temperature and different formations of thermophysical properties was seriously affected by the IPS and exploitation period, which was summarized in detail.