Building new roads has the potential to change the natural patterns of flood flow and increase the risk of flooding in adjacent areas. This study investigated the effects of an expressway on the change in flood inundation in the Tra Khuc–Ve River basin in Vietnam. Because of the presence of reservoirs in the study area, various hydraulic, hydrological, and reservoir operational models were employed. Regarding flood flow, scenarios with frequencies of 1, 3, 5, 10, and 20% were used. The comparison of simulated and observed flood trace data shows good agreement. The distribution of floods has changed a lot, as shown in the inundation maps. The new expressway has caused serious flooding in some areas. The water level difference between the two sides of the road can be as high as 2 m. The flooding duration at several locations increased by many hours. In addition, several structural measures are also suggested to lessen the effects of floods, such as dredging rivers, constructing flood drainage canals, and adding more culverts. Lastly, shortcomings in Vietnam's road construction guidelines in flood zones are also mentioned.