This paper presents a decision support system (DSS) for sustainable development and environmental protection of agricultural regions developed in the framework of the Interreg-Archimed project entitled WaterMap (development and utilization of vulnerability maps for the monitoring and management of groundwater resources in the ARCHIMED areas). Its aim is to optimize the production plan of an agricultural region taking in account the available resources, the environmental parameters, and the vulnerability map of the region. The DSS is based on an optimization multicriteria model. The spatial integration of vulnerability maps in the DSS enables regional authorities to design policies for optimal agricultural development and groundwater protection from the agricultural land uses. The DSS can further be used to simulate different scenarios and policies by the local stakeholders due to changes on different social, economic, and environmental parameters. In this way, they can achieve alternative production plans and agricultural land uses as well as to estimate economic, social, and environmental impacts of different policies. The DSS is computerized and supported by a set of relational databases. The corresponding software has been developed in a Microsoft Windows XP platform, using Microsoft Visual Basic, Microsoft Access, and the LINDO library. For demonstration reasons, the paper includes an application of the DSS in a region of Northern Greece.