The present study investigated total arsenic (tAs), inorganic arsenic (iAs) species and fluoride ion (F−) contamination in underground water of Mithi and Nangarparkar subdistricts of Tharparkar, Pakistan. Statistical parameters, principal component analysis, cluster analysis, sodium absorption ratio and saturation indices (SI) were used to detect interrelation and sources of concentration of tAs, iAs species (As3+ and As5+), F− and others physicochemical parameters. The concentration of As3+ was measured by cloud point extraction using ammonium pyrrolidinedithiocarbamate (APDC) as complexing reagent, while inorganic arsenic (iAs) was determined by solid phase extraction, using titanium dioxide. The positive correlation was observed between F− contents with As species and other major ions, found in the underground water of the study area. The resulted data indicated that underground water samples of two areas of Tharparkar were severely contaminated with arsenic (0.100–3.83 mg/L) and fluoride ion (13.8–49.3 mg/L), which were exceeded the World Health Organization provisional guideline values, 0.01 mg/L and 1.5 mg/L, respectively. The SI of fluorite and calcite in the underground water samples showed that most of the samples were oversaturated with respect to calcite and fluoride.