Global perspectives on the complexities of environmental change impacts associated with past and present human activity are needed for the food and water security challenges of the twenty-first century. This is especially true for rivers, for which the onset and persistence of a range in human activities, altering their function and form, have been temporally and spatially variable. Ancient civilisations, states and empires extended geographically to cover sub-continental areas where their river modifying activities became linked to regional Earth system stresses arising from climate and land use change. We present a new interpretative framework for characterising and classifying human impact on river systems, emphasising that this has taken place over decadal to millennial time periods on a sub-continental scale. This 16-element classification and documentation of different human transformations, including land management, urbanisation, industry and engineering activities, is used to explore anthropogenic channel and floodplain disruptions that have followed each other in different sequences in different places. It is significant that these inadvertent and deliberate human interventions have also taken place in parallel with contrasting climatic fluctuations that have been sub-continental in scale and varied in time. We assess the influence of the dominant modes of regional climate variability (monsoons, El Niño Southern Oscillation, Indian Ocean Dipole, North Atlantic Oscillation, Pacific Decadal Oscillation and Siberian High) on the speed and pattern of river system adjustment to anthropogenic perturbations. Some river civilisations have proved resilient to change given their adaptive management, while others have been overwhelmed by climate-related changes in river morphodynamics. We conclude that integrated socioeconomic, climatic and hydromorphological histories provide usefully instructive antecedents for sensibly managing, as they evolve, the even more serious coupled environmental stresses likely in the future.