Climatic and hydrologic observations and results from a terrestrial ecosystem model coupled to a regional-scale river-routing algorithm are used to document the associations between the El Niño-Southern Oscillation (ENSO) phenomenon and anomalies in climate, surface water balance, and river hydrology within the Mississippi River basin. While no ENSO signal is found in streamflow at the outlet of the basin in Vicksburg, Mississippi, significant anomalies in all water balance components are found in certain regions within the basin. ENSO is mainly associated with positive winter temperature anomalies, but hydrologic patterns vary with season, location, and ENSO phase. El Niño precipitation anomalies tend to affect evapotranspiration (ET) in the western half of the basin and runoff in the eastern half. La Niña events are associated with ET anomalies in the central portion of the basin and runoff anomalies in the southern and eastern portions of the basin. Both ENSO phases are associated with decreased snow depth. Anomalous soil moisture patterns occur at seasonal time scales and filter noisier spatial patterns of precipitation anomalies into coherent patterns with larger field significance; however, for all water budget components, there is a large amount of variability in response within a particular ENSO phase. With anomalies that are up to 4 times those of a typical event, it is clear that improved predictability of the onset and strength of an upcoming ENSO event is important for both water resource management and disaster mitigation.