Climate conditions in Africa have varied substantially during the Late Quaternary with alternating humid and arid periods controlled mainly by the African monsoonal regime. However, the duration and termination of the last African Humid Period (14–6 ka BP) and its internal climatic variability are still debated. Using a laminated sequence from the Nile Deep-Sea Fan, we reconstruct for the first time the monsoon-induced frequency of exceptional Nile floods at centennial resolution during the African Humid Period. By combining sedimentological, geochemical and microscopic tools and comparing our record with two proximal piston cores and with regional paleoclimatic records, we show: a) the occurrence of recurrent high-energy floods between 10.1 and 9 ka BP, during the height of the African Humid Period; b) a shift in the hydro-climatic regime as early as 9 ka BP, with a progressive reduction in flood frequency and magnitude until 8.2 ka BP, likely related to a southward migration of the monsoon rainfall belt; c) a drastic reduction of flood activity between 8.2 and 7.8 ka BP; d) an unstable Ethiopian-Nile hydrological system from 7.8 ka BP, followed by a further decrease in river runoff until ∼4 ka BP. The occurrence of a stepwise hydro-climatic deterioration over the Ethiopian Highlands from ∼9 ka BP brings into question the climatic linkages and feedbacks between low and high latitudes during the Early to Mid-Holocene and in particular around the 8.2 ka BP North Atlantic cooling event. Our unique record of flood frequency at centennial-resolution therefore allows us to draw new insights on fluvial and geomorphic feedbacks of the Nile hydrologic system to monsoonal regimes during a period of major environmental shifts.