Groundwater is a very important natural resource in Khanyounis Governorate (the study area) for water supply and development. Historically, the exploitation of aquifers in Khanyounis Governorate has been undertaken without proper concern for environmental impact. In view of the importance of quality groundwater, it might be expected that aquifer protection to prevent groundwater quality deterioration would have received due attention. In the long term, however, protection of groundwater resources is of direct practical importance because, once pollution of groundwater has been allowed to occur, the scale and persistence of such pollution makes restoration technically difficult and costly. In order to maintain basin aquifer as a source of water for the area, it is necessary to find out, whether certain locations in this groundwater basin are susceptible to receive and transmit contamination. This study aims to: (1) assess the vulnerability of the aquifer to contamination in Khanyounis governorate, (2) find out the groundwater vulnerable zones to contamination in the aquifer of the study area, and (3) provide a spatial analysis of the parameters and conditions under which groundwater may become contaminate. To achieve that, DRASTIC model within geographic information system (GIS) environment was applied. The model uses seven environmental parameters: depth of water table, net recharge, aquifer media, soil media, topography, impact of vadose zone, and hydraulic conductivity to evaluate aquifer vulnerability. Based on this model and by using ArcGIS 9.3 software, an attempt was made to create vulnerability maps for the study area. According to the DRASTIC model index, the study has shown that in the western part of the study area the vulnerability to contamination ranges between high and very high due to the relatively shallow water table with moderate to high recharge potential, and permeable soils. To the east of the previous part and in the south-eastern part, vulnerability to contamination is moderate. In the central and the eastern part, vulnerability to contamination is low due to depth of water table. Vulnerability analysis of the DRASTIC Model indicates that the highest risk of contamination of groundwater in the study area originates from the soil media. The impact of vadose zone, depth to water level, and hydraulic conductivity imply moderate risks of contamination, while net recharge, aquifer media, and topography impose a low risk of aquifer contamination. The coefficient of variation indicates that a high contribution to the variation of vulnerability index is made by the topography. Moderate contribution is made by the depth to water level, and net recharge, while impact of vadose zone, hydraulic conductivity, soil media, and Aquifer media are the least variable parameters. The low variability of the parameters implies a smaller contribution to the variation of the vulnerability index across the study area. Moreover, the “effective” weights of the DRASTIC parameters obtained in this study exhibited some deviation from that of the “theoretical” weights. Soil media and the impact of vadose zone were the most effective parameters in the vulnerability assessment because their mean “effective” weights were higher than their respective “theoretical” weights. The depth of water table showed that both “effective” and “theoretical” weights were equal. The rest of the parameters exhibit lower “effective” weights compared with the “theoretical” weights. This explains the importance of soil media and vadose layers in the DRASTIC model. Therefore, it is important to get the accurate and detailed information of these two specific parameters. The GIS technique has provided an efficient environment for analysis and high capabilities of handling large spatial data. Considering these results, DRASTIC model highlights as a useful tool that can be used by national authorities and decision makers especially in the agricultural areas applying chemicals and pesticides which are most likely to contaminate groundwater resources.