Climate change and human activity have exerted significant influences on the sediment load and channel morphology of the Changjiang River system, China. However, our knowledge of their influence on flood regime on the centennial to millennial timescales remains limited, and this is mainly because of the difficulty in directly determining the long-term hydrological variability of the Changjiang River over the period before hydrological gauges were established. Based on multiproxy analysis that combines chronological, sedimentological, and geochemical analysis of a 4.8-m-long sediment core retrieved from the subaqueous delta of the Changjiang River, this study establishes a flood history for the Changjiang River during the late Holocene. Our palaeoflood reconstruction revealed 14 multi-decadal periods of extreme floods (19–66 BCE, 25–80, 255–350, 415–475, 550–710, 740–835, 970–990, 1080–1130, 1170–1235, 1275–1390, 1440–1500, 1560–1730, 1810–1830, and 1950–2011 CE). These flood units match well with the observed large floods, documentary records of floods, and sedimentary flood deposits, confirming that the coarse units in the sequence are flood-derived and are regionally representative. Comparing with regional and global palaeoclimate records indicates that major flood events of the Changjiang are strongly modulated by the Asian summer monsoon and the El Niño–Southern Oscillation (ENSO), but that anthropogenic impacts (e.g. artificial channelization and land clearance) have also greatly amplified the flooding frequency over the past 600 yr.