As groundwater found in aquifers is the main reservoir of freshwater for human activity, knowledge of the future response of groundwater to climate change is key for improving water management adaptation plans. We analyse the climate-driven evolution of future levels of unconfined aquifers in the 218 world’s major groundwater basins in global climate simulations following the latest IPCC scenarios, run with models able to capture feedbacks among climate, land use and groundwater. We find a rising of groundwater levels on global average, which is consistent with the projected global intensification of precipitation. This signal presents large regional disparities which mostly match the patterns of precipitation changes. As the climate models we used do not simulate human groundwater withdrawals (irrigation as well as domestic and industrial uses) which represent the other main driver of groundwater levels evolution, we also use FAO maps of present-day irrigated areas and projections of population in 2100 to identify regions where groundwater withdrawals could exacerbate the projected depletion, or even reverse a projected rise into a depletion. Depending on the scenario, we then find a rise (respectively a depletion) of groundwater levels in 2100 over 33[28-39]% to 42[41-45]% (respectively 26[25-32]% to 37[36-40]%) of the area covered by the 218 world’s major groundwater basins. And we estimate that 31[29-36]% to 43[42-44]% of the world’s population could be affected by these groundwater changes, facing either water scarcity issues (for 29[27-33]% to 40[39-40]% of the population), or increased risks of flooding (for 1.7[1.5-2.2]% to 2.2[2.2-2.4]% of the population).