Floods are among the most destructive natural hazards globally, causing extensive socioeconomic losses. The Indus River Basin, one of the world’s largest, has experienced recurrent catastrophic floods; however, the absence of effective early warning systems continues to hinder timely disaster response. This study addresses this gap by analyzing extreme flood hazards along the 434-km Chashma–Kot Mithon reach using a one-dimensional HEC-RAS v6.3.0 model integrated with GIS, subdivided into Chashma–Taunsa and Taunsa–Kot Mithon sections. Annual peak flows from 2005 to 2022 were evaluated using the Generalized Extreme Value (GEV) distribution, selected through Kolmogorov–Smirnov and Anderson–Darling tests, to estimate discharges for multiple return periods. The Copernicus GLO-30 Digital Elevation Model (30 m resolution) was refined in the HEC-RAS Mapper by incorporating control structures and bathymetric data to enhance the hydraulic accuracy of the model terrain. Calibration with the 2010 flood and validation with the 2006 flood demonstrated strong performance using differentiated Manning’s n values (channel: 0.027; right bank: 0.055; left bank: 0.040), achieving NSE = 0.92–0.95, R² = 0.91–0.95, and RSR = 0.28–0.20. The 200-year scenario produced peak flows of 31,728 m³/s at Chashma and 28,723 m³/s at Taunsa, increasing inundation by 20.87% and 40.60%, respectively, compared to 2010. MODIS-based validation indicated acceptable accuracy, with overestimations of 8.86% and 4.87%, respectively. Hydrodynamic analysis revealed peak depths of 17 m and velocities of 4 m/s. District-scale assessment showed 10–11% inundation growth in Layyah and Muzaffargarh, whereas union council maps delineated high-risk and safe zones. These findings underscore the potential of HEC-RAS and GIS for proactive flood-risk management in the Indus Basin.