In this study, we explore the long-term trends of floodplain population dynamics at different spatial scales in the contiguous United States (U.S.). We exploit different types of datasets from 1790–2010—i.e., decadal spatial distribution for the population density in the US, global floodplains dataset, large-scale data of flood occurrence and damage, and structural and nonstructural flood protection measures for the US. At the national level, we found that the population initially settled down within the floodplains and then spread across its territory over time. At the state level, we observed that flood damages and national protection measures might have contributed to a learning effect, which in turn, shaped the floodplain population dynamics over time. Finally, at the county level, other socio-economic factors such as local flood insurances, economic activities, and socio-political context may predominantly influence the dynamics. Our study shows that different influencing factors affect floodplain population dynamics at different spatial scales. These facts are crucial for a reliable development and implementation of flood risk management planning.