As the world’s population grows and diets become more diverse, the demand for food has increased and the use of non-renewable resources to produce it has skyrocketed. In this context, the new Water-Energy-Food Nexus approach has been developed to achieve sustainability by balancing the different objectives, benefits, and needs of communities and the environment. In this context, the new Water-Energy-Food Nexus approach has been developed to achieve sustainability by balancing the different objectives, benefits, and needs of communities and the environment. This approach is based on quantifying the relationships between water, food, and energy through qualitative and quantitative modeling and advancing research for integrated resource management. A key mechanism of this approach is to prevent the implementation of inappropriate single-sectoral policies in crop production. Therefore, mathematical programming models play an important role in setting multiple objectives and achieving comprehensive results. This chapter aims to present a multi-objective mathematical programming model using the WEF nexus approach to achieve sustainable agricultural development. This model can identify the complex and interrelated relationships among available resources, leading to more comprehensive programs, decisions, and policies in water, food, and energy security. Ultimately, it guides the country in overcoming barriers and challenges to long-term sustainability. In addition to discussing the general characteristics and types of mathematical programming models, this chapter elaborates on the development and optimization of these models based on the systemic approach, providing a practical example. Finally, the economic and environmental benefits of this method for sustainable agricultural development are evaluated.