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Understanding water storage changes within the Nile’s main sub-basins and the related impacts of climate variability is an essential step in managing its water resources. The Gravity Recovery And Climate Experiment (GRACE) satellite mission provides a unique opportunity to monitor changes in total water storage (TWS) of large river basins such as the Nile. Use of GRACE-TWS changes for monitoring the Nile is, however, difficult since stronger TWS signals over the Lake Victoria Basin (LVB) and the Red Sea obscure those from smaller sub-basins making their analysis difficult to undertake. To mitigate this problem, this study employed Independent Component Analysis (ICA) to extract statistically independent TWS patterns over the sub-basins from GRACE and the Global Land Data Assimilation System (GLDAS) model. Monthly precipitation from the Tropical Rainfall Measuring Mission (TRMM) over the entire Nile Basin are also analysed by ICA. Such extraction enables an in-depth analysis of water storage changes within each sub-basin and provides a tool for assessing the influence of anthropogenic as well as climate variability caused by large scale ocean–atmosphere interactions such as the El Niño Southern Oscillation (ENSO) and the Indian Ocean Dipole (IOD). Our results indicate that LVB experienced effects of both anthropogenic and climate variability (i.e., a correlation of 0.56 between TWS changes and IOD at 95% confidence level) during the study period 2002–2011, with a sharp drop in rainfall between November and December 2010, the lowest during the entire study period, and coinciding with the drought that affected the Greater Horn of Africa. Ethiopian Highlands (EH) generally exhibited a declining trend in the annual rainfall over the study period, which worsened during 2007–2010, possibly contributing to the 2011 drought over GHA. A correlation of 0.56 was found between ENSO and TWS changes over EH indicating ENSO’s dominant influence. TWS changes over Bar-el-Ghazal experienced mixed increase–decrease, with ENSO being the dominant climate variability in the region during the study period. A remarkable signal is noticed over the Lake Nasser region indicating the possibility of the region losing water not only through evaporation, but also possibly through over extraction from wells in the Western Plateau (Nubian aquifer). [ABSTRACT FROM AUTHOR]