This paper presents the first application and validation of a 2D hydrodynamic model of the Amazon at a large spatial scale. The simulation results suggest that a significantly higher proportion of total flow is routed through the floodplain than previously thought. We use the hydrodynamic model LISFLOOD-FP with topographic data from the Shuttle Radar Topography Mission to predict floodplain inundation for a 240 × 125 km section of the central Amazon floodplain in Brazil and compare our results to satellite-derived estimates of inundation extent, existing gauged data and satellite altimetry. We find that model accuracy is good at high water (72% spatial fit; 0.99 m root mean square error in water stage heights), while accuracy drops at low water (23%; 3.17 m) due to incomplete drainage of the floodplain resulting from errors in topographic data and omission of floodplain hydrologic processes from this initial model.