Sanghar District is located in the central part of Sindh Province and shares a boarder with India to the east. This work examines the water quality of the groundwater of three subdistricts, Sanghar, Khipro, and Jan Nawaz Ali, mostly used for human consumption, cattle farming, and irrigation. A total of 74 representative samples were collected and analyzed for 26 different parameters, including anions, cations, trace, and toxic elements. The total dissolved salts (TDSs) contained in 41 samples (55.4%), the major cations, K, Na, Mg, and Ca, in 44.6–93.2% of samples, and the major anions, Cl, HCO3, and SO4, in 68.6–81.0% of samples were within the permissible guidelines of the World Health Organization (WHO). The samples containing elements Cr (24.0%), Pb (29.7%), Ni (39.2%), Cd (40.5%), As (10.8%), and F (39.18%) were above the permissible limits of the WHO. The groundwater samples were examined for water quality index (WQI), contamination index (Cd), chronic daily intake indices (CDIs), hazard quotient indices (HQ), principal component analysis (PCA), piper diagrams, Gibbs diagrams, and cluster analysis to ascertain nature of the groundwater present in the study area. The samples were also examined for suitability for irrigation by sodium percentage (Na%), sodium adsorption ratio (SAR), Kelly’s index (KI), permeability index (PI), and Wilcox diagrams. Samples in the range of 0 to 58.33% were inappropriate for irrigation.