A groundwater monitoring and modeling program in two aquifers within the lower Nestos river basin in Northern Greece is presented. A monitoring network of 54 wells was developed in the two study areas, and groundwater level measurements and water quality sample analyses were conducted for a period of 2.5 years, from March 2007 to October 2009. The field data were used for the calibration and verification of the mathematical model MODFLOW in the two aquifers. The validated model was used to examine ten alternative management scenarios regarding groundwater abstraction in the two aquifers. The study showed that MODFLOW, if properly validated, is a useful and flexible tool in groundwater resources management.