To understand the potential risk of flooding in Syracuse City, New York State, USA, this research attempted to accomplish the flood hazard assessment for a simulated 500-year flood event in the downstream floodplain of Onondaga Creek within Syracuse. Based on the commonly used category of flood damages, the flood damage of Syracuse was divided into loss of buildings and loss of population. The results showed that the city’s center would have the highest damage rate for buildings and a total of 1139 buildings would be inundated, of which 326 buildings would be severely damaged by more than 80%. Furthermore, about 7390 people would be directly affected by the flood event, among which approximately 900 people might lose their lives. Communities near Onondaga Creek were assigned designated evacuation shelters based on the accessibility and distance to the shelters. The shortest available evacuation routes were calculated. More shelters should be provided in the central downtown area, with its large population, and distributed along the western bank of Onondaga Creek. This research offered a first approximate flood loss estimation that might lead to more attention and studies concerning a potential flood hazard in the future. It also provided science-based guidelines for city authorities to refer to in practical flood hazard mitigation.