The efficient exploitation of geothermal energy through enhanced geothermal systems (EGS) has been a relevant topic for hot dry rock (HDR) geothermal resources. When cryogenic fluid is injected into a thermal reservoir, improving heat exchange efficiency is key to achieving the optimal exploitation of HDR. In this paper, granite outcrops from Gonghe Basin were used as the testing sample. The natural fractures in the granite samples were relatively well developed. To simulate long-term injection and production from multi-wells in situ, physical experiments were performed in a newly-developed, in-house large-scale true triaxial experimental system. Geothermal extraction performance of an HDR was simulated for long-term injection and production operations. Simultaneously, the mode of one-injection and multiple-production wells was represented. In the paper, the effects of the production-injection well spacing, the number of production wells and the injection rate on the production temperature and flow rate are discussed. The results show that, during long-term injection and production, there are two stages of production temperature variation, namely stabilization and attenuation. When the number of the production wells is increased, the heat extraction efficiency is accelerated. Moreover, competitive diversion of fluid among fractures occurred due to different conductivities. Furthermore, under different production modes, the production flow rate contributed differently to the heat extraction. Finally, the effect of the production-injection wells spacing on the heat exchange performance was analyzed; this is mainly reflected in the change of the effective heat exchange area between the rock and the injected fluid. The results emphasize the importance of designing an appropriate production mode and optimizing the injection-production parameters to ensure efficient HDR exploitation.