Newberry Volcano in Central Oregon is the site of a Department of Energy funded Enhanced Geothermal System (EGS) Demonstration Project. Stimulation and production of an EGS is a strong perturbation to the physical and chemical environment, giving rise to coupled Thermal-Hydrological-Mechanical-Chemical (THMC) processes leading to permeability changes as a result of mineral dissolution and precipitation, rock deformation, and fracture reactivation. To evaluate these processes, and to help guide EGS stimulation and reservoir development strategies, a combined native-state and reservoir model of the west flank of Newberry Volcano was created that encompasses the planned stimulation zone and a several km region of the west flank from the surface down to the supercritical region, likely close to a postulated cooling intrusive body. Temperature and pressure distributions were first modeled using TOUGHREACT with boundary conditions estimated from nearby drill holes, and compared to measurements made in the over 3 km deep NWG 55-29 drill hole. With estimates of the porosity and heat capacities for the major hydrogeologic units, thermal conductivities were calibrated by matching to the measured temperature profile. To simulate the development of the observed hydrothermal mineralogy, a reaction-transport model (THC) was developed using the pre-alteration mineralogy and shallow groundwater chemistry as the initial geochemical conditions, assuming that modeled temperature and pressure distributions were relatively constant over several thousand years. Close correspondence of modeled and observed epidote distributions support the observation that past hydrothermal activity took place under thermal gradients similar to current values, whereas calcite and sulfide abundances at depth likely require a magmatic gas component. Multicomponent geothermometry was used to estimate potential temperatures of equilibration of waters, and to evaluate the effects of kinetics on calculated mineral equilibration temperatures. The ultimate goal will be to capture both the local chemical and mechanical changes in the rock owing to stimulation as well as the potential long-term response and sustainability of the larger-scale geothermal reservoir.