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This study presents a global explanatory analysis of the interplay between the severity of flood losses and human presence in floodplain areas. In particular, we relate economic losses and fatalities caused by floods during 1990-2000, with changes in human population and built-up areas in floodplains during 2000-2015 by exploiting global archives. We found that population and built-up areas in floodplains increased in the period 2000-2015 for the majority of the analyzed countries, albeit frequent flood losses in the previous period 1990-2000. In some countries, however, population in floodplains decreased in the period 2000-2015, following more severe floods losses that occurred in the period 1975-2000. Our analysis shows that (i) in low-income countries, population in floodplains increased after a period of high flood fatalities; while (ii) in upper-middle and high-income countries, built-up areas increased after a period of frequent economic losses. In this study, we also provide a general framework to advance knowledge of human-flood interactions and support the development of sustainable policies and measures for flood risk management and disaster risk reduction.