The management and monitoring of the quality of water resources in the Mekelle area are challenging, due to both geogenic and anthropogenic impacts. The extent of these impacts and the sources of pollution in this area have not been thoroughly investigated. In this article, a mapping of water resources vulnerability was carried out using the DRASTIC method and a modified DRASTIC vulnerability map was produced. Single-parameter and map-removal sensitivity analyses were performed on the relevant rates and weights. A final DRASTIC vulnerability index, varying from 54 to 140, was divided into four vulnerability classes: low (225.7 km2), medium (302.8 km2), high (307.2 km2), and very high (187.6 km2); the values in the parentheses indicate the corresponding areal coverage of each class. Similarly, a modified DRASTIC vulnerability index, ranging from 91 to 192, was divided into four vulnerability classes: low (166.4 km2), medium (266.8 km2), high (338.0 km2), and very high (252.2 km2) Nitrates were used to validate both models. in which moderate positive correlations (with Pearson’s correlation coefficient, r) of 0.681 and 0.702 were calculated for the DRASTIC and modified DRASTIC indices, respectively. A comparison of the two maps showed that significant sources of pollution are located in areas with high to very high vulnerability. The results of this research work can be used for the protection and monitoring of groundwater resources in the Mekelle area.