Floods are brutal, catastrophic natural hazards which affect most human beings in terms of economy and life loss, especially in the large river basins worldwide. The Indus River basin is considered as one of the world’s large river basins, comprising several major tributaries, and has experienced severe floods in its history. There is currently no proper early flood warning system for the Indus River which can help administrative authorities cope with such natural hazards. Hence, it is necessary to develop an early flood warning system by integrating a hydrodynamic model, in situ information, and satellite imagery. This study used Hydrologic Engineering Center–River Analysis System (HEC–RAS) to predict river dynamics under extreme flow events and inundation modeling. The calibration and validation of the HEC–RAS v5 model was performed for 2010 and 2015 flood events, respectively. Manning’s roughness coefficient (n) values were extracted using the land use information of the rivers and floodplains. Multiple combinations of n values were used and optimized in the simulation process for the rivers and floodplains. The Landsat 5 Thematic Mapper (TM), Landsat 8 Operational Land Imager (OLI), Moderate Resolution Imaging Spectroradiometer (MODIS) MOD09A1, and MOD09GA products were used in the analysis. The Normalized Difference Water Index (NDWI), Modified NDWI1 (MNDWI1), and MNDWI2, were applied for the delineation of water bodies, and the output of all indices were blended to produce standard flood maps for accurate assessment of the HEC–RAS-based simulated flood extent. The optimized n values for rivers and floodplains were 0.055 and 0.06, respectively, with significant satisfaction of statistical parameters, indicating good agreement between simulated and observed flood extents. The HEC–RAS v5 model integrated with satellite imagery can be further used for early flood warnings in the central part of the Indus River basin.