This study demonstrates the potential for applying passive microwave satellite sensor data to infer the discharge dynamics of large river systems using the main stem Amazon as a test case. The methodology combines (1) interpolated ground-based meteorological station data, (2) horizontally and vertically polarized temperature differences (HVPTD) from the 37-GHz scanning multichannel microwave radiometer (SMMR) aboard the Nimbus 7 satellite, and (3) a calibrated water balance/water transport model (WBM/WTM). Monthly HVPTD values at 0.25° (latitude by longitude) resolution were resampled spatially and temporally to produce an enhanced HVPTD time series at 0.5° resolution for the period May 1979 through February 1985. Enhanced HVPTD values were regressed against monthly discharge derived from the WBM/WTM for each of 40 grid cells along the main stem over a calibration period from May 1979 to February 1983 to provide a spatially contiguous estimate of time-varying discharge. HVPTD-estimated flows generated for a validation period from March 1983 to February 1985 were found to be in good agreement with both observed arid modeled discharges over a 1400-km section of the main stem Amazon. This span of river is bounded downstream by a region of tidal influence and upstream by low sensor response associated with dense forest canopy. Both the WBM/WTM and HVPTD-derived flow rates reflect the significant impact of the 1982–1983 El Niño-;Southern Oscillation (ENSO) event on water balances within the drainage basin.