Large-scale hydrodynamic models are vital for flood risk assessment and understanding the global water cycle; however, their results can include uncertainties related to model resolution. Few studies have evaluated hydrodynamic models across a range of spatial resolutions, and these have tended to examine only a few variables (e.g., discharge) or to neglect ungauged sites or parameter optimization. We addressed these limitations by comparing Catchment-based Macro-scale Floodplain (CaMa-Flood) model simulations of Amazon River at different spatial resolutions, using the higher resolution as a benchmark in each comparison. We found that the model performed well in simulating discharge and water depth, with coefficients of determination exceeding 0.84 in > 90% of locations. The normalized Nash–Sutcliffe efficiency coefficients for discharge and water depth were greater than 0.80 and 0.64, respectively, in > 80% of locations, suggesting that most locations had consistent hydrodynamics. We detected large discrepancies in discharge between simulations at ~2.5% of locations due to limited representation of bifurcation flow, floodplain conveyance, and backwater at river confluences in the model. Water depth also differed significantly at ~3% of locations, mainly at headwaters, due to width bottleneck sections. Flood extent patterns differed minimally between simulations around the main stream and large sub-streams, whereas improvements in the downscaling method are required for small sub-streams. Our results demonstrate the need to improve the representation of bifurcation channels and floodplain parameterization for specific locations, although the general river hydrodynamics patterns were well-captured by computationally efficient moderate-resolution (i.e., 6 arcmin) CaMa-Flood simulations.