The present study for the first time highlighted the arsenic and heavy metals (HM) concentrations as well as their source of contamination in tube-well water and associated potential health risk to local residents of Tehsil Mailsi (Punjab), Pakistan. 44 samples were collected from Jala Jeem and Dunia Pur. Results revealed average concentrations of anion and heavy metals such as Iron (Fe), (Cadmium) Cd, (Lead) Pb, (Sodium) Na+, (Bicarbonate) HCO3-, (Sulfate) SO42- and Arsenic (As) exceeded the WHO limits in the tube well water. The calculated target hazard quotient (THQ) of metals from local tube well water above 1 was observed for As (36.5) and Cd (6.2), which employed highly potential health risk to local residents. The suitability of water for irrigation is evaluated based on residual sodium carbonate (RSC), sodium adsorption ratio (SAR), Kelly's index (KI), Sodium percent (%Na) and Magnesium absorption ratio (MAR). Dominant ions in the study area are HCO3-, Ca2+ and Mg2+ and water chemistry of the area is Ca2+ -Mg2+ -HCO3- type. However, different statistical tools, including principal component analysis (PCA), hierarchical cluster analysis (CA) and correlation matrices revealed the contribution of both natural as well as anthropogenic activities towards the high level of arsenic and heavy metals contamination in the local tube well water. The results show that consumption of heavy metals contaminated groundwater poses an emerging health threat to the populations in the study area, and hence needs urgent remedial and management measures. Continued monitoring of heavy metals levels is recommended for future management strategies.