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The co-location of desalination plants with existing or proposed power plants can bring forth economic and ecological advantages in terms of reducing the costs of water intake and reducing fish impingement. However, fossil fuel-based power plants are a source of ozone precursors and the added strain of power needed for the energy intensive desalination process increases these pollutants into the atmosphere. Furthermore, withdrawal from brackish water sources puts a stress on slowly replenishing aquifers. Additionally, the resulting concentrate is highly saline and disposal into ecologically sensitive bays and estuaries may be problematic. Balancing these limitations with the need for freshwater is of great importance for sustainability of water scarce arid and semi-arid regions and also requires a holistic multimedia impact evaluation. Therefore, an integrated system of systems approach is adopted in this study and a decision support system that integrates the flow of water, concentrate and resulting pollutants through two engineered (power plant and desalination plant) as well as three natural systems (coastal bay, aquifer and the atmosphere) is developed to study the co-location of a power plant and a desalination plant near the City of Corpus Christi in South Texas. The objective of the model is to minimize the amount of groundwater extraction and minimize the amount of water extracted from the bay to emphasize water and ecosystem conservation, respectively. These objectives, in turn, are subject to various other constraints including (1) conservation of mass; (2) air quality regulations; (3) salinity regulation policies; (4) groundwater management constraints; (5) water demand requirements; and (6) energy demand constraints. The results indicate that when conservation of the aquifer is weighted more, less water is pulled from the aquifer until later time periods. The salinity of the bay increases and creates a need for a greater amount of power necessary to process the saline water which, in turn, enhances the atmospheric loading of ozone precursors. Therefore, the conservation of groundwater scenario is limited by the air quality standards. Alternatively, when the goal is to conserve the ecological integrity of the bay while meeting freshwater demands, the model is bound by the prescribed drawdown constraint that limits the amount of water that can be extracted from the aquifer. The results from the study indicate that blending saline bay water with brackish groundwater and using cleaner burning fossil fuels that have limited air quality impacts will enhance the performance of the co-located power and desalination operations. The results of the study highlight the need for an integrated multimedia evaluation in assessing the feasibility of desalination in areas with marginal air quality.