To examine the hydrological system sensitivity of the southern Sierra Nevada Mountains of California to climate change scenarios (CCS), five headwater basins in the snow-dominated Upper San Joaquin River Watershed (USJRW) were selected for hydrologic simulations using the Hydrological Simulation Program-Fortran (HSPF) model. A pre-specified set of CCS as projected by the Intergovernmental Panel on Climate Change (IPCC) were adopted as inputs for the hydrologic analysis. These scenarios include temperature increases between 1.5 and 4.5 °C and precipitation variation between 80 and 120% of the baseline conditions. The HSPF model was calibrated and validated with measured historical data. It was then used to simulate the hydrologic responses of the watershed to the projected CCS. Results indicate that the streamflow of USJRW is sensitive to the projected climate change. The total volume of annual streamflow would vary between −41 and +16% compared to the baseline years (1970–1990). Even if the precipitation remains unchanged, the total annual flow would still decrease by 8–23% due to temperature increases. A larger portion of the streamflow would occur earlier in the water year by 15–46 days due to the temperature increases, causing higher seasonal variability of streamflow.