A fan-wide assessment of modern depositional processes on the Río Grande (Guapay) megafan, coupled with the analysis of its Holocene evolution, reveals that most of the 36,000 km2 megafan surface has been subject to sedimentation processes and/or reworking in the last 6–7 ka. Today, depositional dynamics as inferred from multi-date satellite imagery are mostly restricted to a ~ 2,000 km2 depozone on the distal megafan, and are characterised by avulsive fluvial environments. Combining remote sensing with field observations and geochronology at key locations has allowed to capture links between the dynamics of depositional processes and larger-scale landforms, documenting significant changes in the location of the depozone since ~ 4 ka. On shorter time scales, the human impact on these dynamic sedimentary processes is expressed by artificial levees and re-channelisation following crevasse splays. This is likely to have prevented a number of channel avulsions over the last decades and implies that the use of modern avulsion frequencies and depositional rates alone as analogues for understanding Holocene megafan evolution is of limited use. Instead, our observations emphasise the increasing vulnerability to future avulsion events within an intrinsically unstable fluvial environment that has seen rapid deforestation and population growth in recent time.