Climate and land use change (global change) impacts on groundwater systems cannot be studied in isolation. Land use and land cover (LULC) changes have a great impact on the water cycle and contaminant production and transport. Groundwater flow and storage are changing in response not only to climatic changes but also to human impacts on land uses and demands, which will alter the hydrologic cycle and subsequently impact the quantity and quality of regional water systems. Predicting groundwater recharge and discharge conditions under future climate and land use changes is essential for integrated water management and adaptation. In the Mancha Oriental system (MOS), one of the largest groundwater bodies in Spain, the transformation from dry to irrigated lands during the last decades has led to a significant drop of the groundwater table, with the consequent effect on stream-aquifer interaction in the connected Jucar River. Understanding the spatial and temporal distribution of water quantity and water quality is essential for a proper management of the system. On the one hand, streamflow depletion is compromising the dependent ecosystems and the supply to the downstream demands, provoking a complex management issue. On the other hand, the intense use of fertilizer in agriculture is leading to locally high groundwater nitrate concentrations. In this paper we analyze the potential impacts of climate and land use change in the system by using an integrated modeling framework that consists in sequentially coupling a watershed agriculturally based hydrological model (Soil and Water Assessment Tool, SWAT) with a groundwater flow model developed in MODFLOW, and with a nitrate mass-transport model in MT3DMS. SWAT model outputs (mainly groundwater recharge and pumping, considering new irrigation needs under changing evapotranspiration (ET) and precipitation) are used as MODFLOW inputs to simulate changes in groundwater flow and storage and impacts on stream-aquifer interaction. SWAT and MODFLOW outputs (nitrate loads from SWAT, groundwater velocity field from MODFLOW) are used as MT3DMS inputs for assessing the fate and transport of nitrate leached from the topsoil. Three climate change scenarios have been considered, corresponding to three different general circulation models (GCMs) for emission scenario A1B that covers the control period, and short-, medium-and long-term future periods. A multi-temporal analysis of LULC change was carried out, helped by the study of historical trends (from remote-sensing images) and key driving forces to explain LULC transitions. Markov chains and European scenarios and projections were used to quantify trends in the future. The cellular automata technique was applied for stochastic modeling future LULC maps. Simulated values of river discharge, crop yields, groundwater levels and nitrate concentrations fit well to the observed ones. The results show the response of groundwater quantity and quality (nitrate pollution) to climate and land use changes, with decreasing groundwater recharge and an increase in nitrate concentrations. The sequential modeling chain has been proven to be a valuable assessment tool for supporting the development of sustainable management strategies.