The increase in world population, added to socioeconomic development and climate change, have highlighted one of the biggest problems worldwide: the depletion of water resources. The La Ligua and Petorca river basins, in central Chile, are an example of this problem, as rainfall has decreased in recent years, while socio-economic activities, mainly agriculture have increase. This situation has led to a severe water stress, and the need for integrated and sustainable river basin management, aimed at understanding the behavior of basins, aquifers, and the exchange of flows between them. Therefore, the main objective of this research is to quantify the impacts of climate change, in terms of groundwater scarcity, in semi-arid basins using integrated modeling of water resources. For this purpose, groundwater/surface waters integrated models of La Ligua and Petorca basins were developed using WEAP and MODFLOW. Both basins present different hydrological, social, and geographical characteristics. Different scenarios were evaluated to quantify groundwater depletion. These scenarios depend on climatic forcings, such as precipitation and temperature, which were obtained from the Phase 6 of the Coupled Model Intercomparison Project (CMIP6). Results forecast that annual precipitation will decrease, whereas average annual temperature will increase in these semi-arid regions. As a consequence, the aquifer’s recovery rate will reduce, decreasing the number of wells that provide drinking water in rural and agricultural areas. In conclusion, the coupling of hydrological and hydrogeological models is a tool that allows researchers and stakeholders to make opportune and appropriate decisions on the management of basins and aquifers, which is even more important in basins that are expected to be or are already under severe water stress.