A major flood event occurred on 21 August 2020 in the densely populated Makepe Missoke neighborhood in the city of Douala (Cameroon, Africa). Nearly 2210 buildings and 12,376 victims spread over 82 hectares were affected. A 2D HEC-RAS model is applied to simulate and characterize this event. A cross analysis of flood depth and flow velocity is used to classify the flood risk and identify areas exposed from low to high hazard. The simulations provide detailed information on the flood characteristics (extent, depth, velocity, arrival time, and duration). The simulated maximum water surface profiles are consistent with the floods marks with differences ranging from 0.02 m to 0.44 m, indicating a good agreement between the observed and simulated water levels at the peak flow (NSE = 0.94, Erel = 0.92, RMSE = 0.21 m). The maximum inundation level is 4.48 m and the flow velocity is globally low at less than 1 m/s. The average flood arrival time and duration are 5 h and 26 h, respectively, for a threshold height of 0.5 m. These results indicate a fast mobilization of the major river channel for the evacuation of this flood. The level of accuracy of the developed model of the 21 August 2020 flood event is appropriate for flood hazard assessment in the city of Douala and is designed to find operational application in future events.