Changes in major climatic and hydrological quantities in the upper Mississippi River basin and their interrelationships are studied with the Soil and Water Assessment Tool being driven by the contemporary climate and future scenario simulations of 10 global models in the Intergovernmental Panel on Climate Change (IPCC) Data Archive. Although the seasonal cycles of climate and hydrological quantities simulated by the 10 models have differences, the ensemble is very close to the observation. Ensemble predictions show that with warming in all months, precipitation decreases in summer but increases in all other seasons. Correspondingly, streamflow decreases in all seasons except winter, evapotranspiration decreases in July–September and increases in all other months, and snowmelt increases in winter but decreases in spring and fall. To understand the linkages between the cross-century changes of climate and hydrological quantities and the relative importance of the changes of temperature and precipitation to the changes of hydrological quantities, relationships between interannual variations of these quantities are investigated. It is shown that the change rates of the hydrological quantities with respect to temperature and precipitation obtained from regressions of interannual variations can vary greatly from month to month; however, on a monthly basis, they do not change much from the current to the future periods. Evaluations with these change rates indicate that for interannual variations of hydrological quantities, both variations of temperature and precipitation are important, and their relative importance depends on the month of the year. However, the changes of hydrological quantities from the means of the current years to the means of the future are dominated by warming in all months, and the influence from change of precipitation is much smaller. The changes of the hydrological quantities can be well predicted with the change rates from the warming alone.