Optimizing escape routes during an extreme flood event is an effective way to mitigate casualties. In this study, a model for selecting optimal escape routes in a flood-prone area has been proposed, which includes a module for predicting the two-dimensional hydrodynamics and modules for assessing the hazard degree for evacuees, calculation of evacuation times and determination of different escape routes. In the module for determining escape routes, two evacuation schemes were used: Scheme A to find optimal escape routes based on established road networks, and Scheme B to design a new optimal evacuation route. Extreme overbank floods occurred in the Lower Yellow River (LYR) in July 1958 (‘58.7’) and August 1982 (‘82.8’) and the proposed model was applied to select the optimal escape routes on a typical floodplain area of the LYR for these two floods. Model predictions indicated that: (i) the optimal escape routes for these two floods were the same for all three starting locations, and the optimized routes provided 3 h more time for evacuees to escape; and (ii) the time of evacuation would need to be earlier for the ‘58.7’ flood because of its larger amount of water volume and higher peak discharge.