During the Messinian salinity crisis (5.96–5.33 Ma), the Mediterranean Sea was disconnected from the Atlantic Ocean. As a consequence, a dramatic sea-level fall occurred during part of the crisis and deep erosion has been observed on the Mediterranean margins as well as on the continent. Here, we demonstrate that the erosion and the large sea-level fall generated a significant uplift along the Nile River delta valley, due to isostatic rebound. Based on a quantitative analysis, our results suggest that the uplift of the Egyptian margin and of the Nile valley flanks may have triggered an enclosed environment during the Messinian salinity crisis (MSC). We estimated a mean rate of regressive erosion of −2.5 m/y along the River Nile during the MSC and of 1.25 and 0.4 m/y for the smaller rivers. The water discharge of the River Nile necessary to trigger this erosion rate was at least 5 to 25 times superior than the water discharge of the smaller one’s.