The Sanjin deposit is one of three major ore zones hosted by Pleistocene quartz-adularia veins being mined at the Hishikari low-sulfidation epithermal gold mine, which has produced more than 242 t of gold at an extraordinary average grade since 1985. Hydrothermal alteration zoning of the Sanjin deposit was examined with respect to mineralogy, geochemistry, fluid inclusion microthermometry, and oxygen and hydrogen isotopes. Clay minerals are dominated by interstratified chlorite-smectite (C/S) and interstratified illite-smectite (I/S) with <20% smectite. Epidote and prehnite are recorded for the first time at Hishikari in the southeastern part of the Sanjin deposit, typically coexisting with chlorite. Trapping temperatures of fluid inclusions from associated ore zone quartz veins typically range from 195 to 230 °C, with higher temperatures prevalent in the southeastern part of the Sanjin deposit. The calculated fluid δ18O and δ2H values from clay minerals and quartz cannot be explained by a simple water-rock interaction or a simple fluid mixing model, since variable isotopic exchange temperature and endmembers have to be considered. This suggests that both water-rock interaction and mixing of fluids occurred between dynamically variable end members during mineralization. The average estimated formation temperature of chlorites in the Sanjin deposit using chlorite geothermometry is 233 ± 19 °C, in agreement with the highest temperature zone in Hishikari, estimated by homogenization temperature of fluid inclusions of ore veins. In addition, the estimated formation temperatures of chlorite in epidote- and/or prehnite-rich altered rocks are higher (avg. 240 ± 17 °C) than those in epidote- and/or prehnite-poor altered rocks (avg. 216 ± 9 °C). Thus, the chlorite-epidote/prehnite assemblage can be an index of a high temperature alteration zone in the Sanjin deposit. Considering the position of the paleo-water table of the three ore zones, these factors are consistent with the formation of the Sanjin deposit proximal to the upflow zone responsible for gold mineralization at Hishikari. We suggest that our approach could be utilized to understand the thermal structure of epithermal gold system, which may be important to explore for blind veins at mature mining districts.