This paper constitutes an assessment of the climate change (CC) impacts on the Zeuss–Koutine (ZK) aquifer in southeastern Tunisia using a WEAP-MODFLOW decision support system (DSS). Efficiency criteria are calculated for hydraulic heads to validate the MODFLOW model. The DSS simulates the behavior of the aquifer while representing demands and other water sources. It is able to evaluate monthly water management scenarios up to 2030. It emphasizes the seriousness of the water resource situation in the region exhausted by the increasing demands and the climate circumstances which leads to the risk of salinization. The DSS shows a calculated aquifer drawdown during the simulation period (1982–2010) of 22.0 m which is exactly the recorded one. To simulate future CC, data are collected from the “Climate Wizard” web site, providing results of 16 general circulation climate models under A2, A1B, and B1 emission scenarios. Based on precipitation changes, three scenarios are deduced: the mean, the worst, and the best CC. Results show that the forecasted average drawdown (2010–2030) would be between 30.5 (1.5 m/year) and 33.9 m (1.7 m/year) under the best and the worst CC scenarios, respectively. The worst CC scenario could lead to the intrusion of brackish lagoon water or even a long-term marine intrusion. The use of the Jerba Sea Water Desalinization Plant (JSWDP), in 2018, would improve the situation, and the average estimated drawdown would be 16.9 m (0.8 m/year) under the mean CC, presenting then an improvement of about 49%. The ZK aquifer would lose 121% of its storage under the coupled JSWDP_mean CC scenario, between 1982 and 2030, presenting an improvement of about 52% compared to CC scenarios.