Due to increasing water stress, especially in arid and semi-arid regions, the importance of using modern technologies for optimal water consumption in the agricultural sector has increased. This study aimed to evaluate the performance and sustainability of greenhouses equipped with reverse osmosis (RO) desalination systems within the framework of the Water, Food, Energy and Environment (WEFE) Nexus in the Pakdasht region of Iran. The research method was descriptive-analytical and the necessary information was collected using a questionnaire and field observations. In this study, 15 greenhouses (8 with RO and 7 without) were studied in three scenarios based on energy supply and water purification. The results showed that greenhouses with RO saved an average of 19% in water consumption and increased crop yield by 18.9%. Also, the consumption of chemical fertilizers and pesticides showed a decrease of 21.4% and 31%, respectively. However, there was an increase in costs related to the energy sector and the maintenance of these systems. According to the results of the scenario analysis, the use of solar energy as an alternative source of grid electricity can lead to a reduction in costs and greenhouse gas emissions. The final analysis within the WEFE framework showed that the RO system, when properly designed and combined with renewable energies, can play an effective role in increasing the resilience of agriculture in water-scarce regions.