This study aims to evaluate the vulnerability of shallow aquifer in irrigated and coastal regions of Sindh province, Pakistan by applying DRASTIC method in GIS environment. Vulnerability index values ranging from 119 to 200 were categorized into three contamination risk zones. Results illustrated that 28.03% of the total area that was distributed in the upper northern and southernmost coastal area of the province was very highly vulnerable to contamination, 56.76% of the area was highly vulnerable, while the remaining 15.21% area was in medium vulnerable zone. Single and multi-parameter sensitivity analysis evaluated the relative importance of each DRASTIC parameter and illustrated that depth to water table and net recharge caused the highest variation in the vulnerability index. Two water quality indicators parameters, i.e., electrical conductivity (EC) and nitrate ion (NO3−) were used to validate the DRASTIC index. The spatial distribution map of both parameters showed a certain level of similarity with the vulnerability map and both parameters illustrated significant correlation with the DRASTIC vulnerability index (p < 0.01). This signified that vulnerable zones are particularly more prone to EC and NO3− contamination. Findings of this study will assist local authorities in contamination prevention in the groundwater of the lower Indus Plain.