Flooding is one of the leading challenges faced by delta cities in the world. Flood risk management using flood control infrastructure (FCI) is a popular solution to prevent flood damage; however, this is receiving enormous criticism due to its negative impacts on urban ecosystems. Recently, there have been new approaches to flood risk management that gradually shifted the focus away from FCI, such as ecological infrastructure (EI) based approaches. However, the conventional thinking that cities cannot be safe without FCI seems an immutable one, especially in developing countries. This study firstly assessed human–river interaction in direct relation to FCI and outlined the limitations of FCI. Then, an urban ecology research model was used to conduct a case study in the Vietnamese Mekong Delta (VMD), in which the interaction between factors, including riverine urbanization, FCI formation dynamics, the changing hydrological regime, flood risk, and riverine ecosystem degradation were evaluated. Due to the dynamism and complexity of the interactions between humans and rivers at the VMD, this study attempts to demonstrate that building the ability to adapt to flood risks based on EI will have a crucial role in enhancing the sustainability of delta cities. Through a case study in My Tho City (MTC) a flood resilience management scenario for a riverine urban area along the Mekong River was developed to discuss the role of EI in flood risk reduction and the restoration of riverine native ecosystems. The findings from this study suggests that EI should be considered as an effective and indispensable design tool for the conservation of riparian ecological corridors and public open spaces—which is a major challenge for urban areas in the context of increasing climate change impacts in the VMD.