Quantifying the hydrological response to an increased atmospheric CO2 concentration and climate change is critical for the proper management of water resources within agricultural systems. This study modeled the hydrological responses to variations of atmospheric CO2 (550 and 970 ppm), temperature (+1.1 and +6.4 °C), and precipitation (0%, ±10%, and ±20%) based on Intergovernmental Panel on Climate Change projections. The Soil and Water Assessment Tool (SWAT) was used to model the hydrology and impact of climate change in the highly agricultural San Joaquin watershed in California. This watershed has an area of 14,983 km2 with a Mediterranean climate, resulting in a strong dependence on irrigation. Model calibration (1992–1997) and validation (1998–2005) resulted in Nash–Sutcliffe coefficients of 0.95 and 0.94, respectively, for monthly stream flow. The results of this study suggest that atmospheric CO2, temperature and precipitation change have significant effects on water yield, evapotranspiration, irrigation water use, and stream flow. Increasing CO2 concentration to 970 ppm and temperature by 6.4 °C caused watershed-wide average evapotranspiration, averaged over 50 simulated years, to decrease by 37.5%, resulting in increases of water yield by 36.5%, and stream flow by 23.5% compared to the present-day climate. Increasing temperature caused a temporal shift in plant growth patterns and redistributed evapotranspiration and irrigation water demand earlier in the year. This caused an increase in stream flow during the summer months due to decreased irrigation demand. Water yield, however, decreased with an increase in temperature. Increase of precipitation by ±10% and ±20% generally changed water yield and stream flow proportionally, and had negligible effects on predicted evapotranspiration and irrigation water use. Overall, the results indicate that the San Joaquin watershed hydrology is very sensitive to potential future climate changes. Agricultural implications include changes to plant growth rates, irrigation timing and runoff, all of which may affect future water resources and water quality.