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We develop a water budget model that quantifies and forecasts water deficits and groundwater depletion of the main exploitable fresh fossil aquifer systems in North Africa and the Arabian Peninsula under different climatic and socio-economic scenarios from 2016 until 2050. Our results suggest that in the upcoming few decades, under the most plausible climatic and socio-economic scenario (SSP2-AVG), within North Africa, only Egypt and Libya will experience severe water deficits with respectively similar to 45% and similar to 90% of their current water budget in 2050. For the Arabian Peninsula, all countries will undergo water deficits, ranging from similar to 20% for Saudi Arabia to almost double the supply for Yemen (similar to 190%). Under these alarming deficits, resulting from severe anthropogenic discharges, the majority of the small to mid-size exploitable fossil aquifer systems in the Arabian Peninsula could reach full depletion by 2050 and the total depletion of groundwater resources in all aquifer systems could be reached in similar to 60-90 years. Over the same time span, North African fossil aquifers will lose 1-15% of their exploitable fresh water volume and may reach total depletion in similar to 200-350 years with the projected increased extraction rates. We find that the major cause of the water budget deficit and groundwater depletion in the MENA area are anthropogenic drivers rather than climatic ones. Finally, we conclude that if current hydrologic, climatic and socio-economic trends continue, the nations with the lowest gross domestic product per capita, like Egypt, Yemen and Libya, will undergo the highest water deficit per capita, leading to a significant rise in food prices, potentially resulting in more socio-economic instabilities over the next three decades.