In central Tunisia, near the city of Kairouan, the Merguellil catchment illustrates the multiple forms of the global change affecting Mediterranean water resources. In this semi-arid region, climatic fluctuations have always constrained the water resources, but anthropization has become by far the most influential driver of change in the last century. Environmental and social components of this fragile system continuously interact and adapt to multiple internal and external stresses (including demographic pressure and economic development). Long-term hydrological monitoring, the analysis of historical archives, surveys among the population and water managers reveal the multiple steps to the present state of general groundwater depletion. In the upstream part of the catchment, the numerous water and soil conservation works significantly reduce surface runoff and river flow, which increases withdrawals for irrigation and the groundwater overexploitation since one century to meet the coastal water demand. The large El Haouareb dam definitively prevented the direct recharge of the Kairouan plain aquifer through floods, and created a new recharge location and process. Downstream, the intense development of irrigation in the Kairouan plain relies exclusively on the large and thick Neogene aquifer, contributing to the continuous decrease of the water table (0.5 / 1 m per year). The various long term data sets outlined the spatio-temporal heterogeneity, the complex modifications of groundwater recharge, and the co-evolutions of water users and uses. Many uncertainties still remain, especially regarding the water balance, the influence of extreme climatic events and the groundwater quality, limiting accurate forecasts for the next decades.