Water quality of the Indus River around the upper basin and the main river was evaluated with the help of statistical analysis. In order to analyze the similarities and dissimilarities for identifying the spatial variations in water quality of the Indus River and sources of contamination, multivariate statistical analysis, i.e., principle component analysis (PCA), cluster analysis, and descriptive analysis, was done. Data of 8 physicochemical quality parameters from 64 sampling stations belonging to 6 regions (labeled as M1, M2, M3, M4, M5, and M6) were used for analysis. The parameters used for assessing the water quality were pH, dissolved oxygen (DO), oxygen reducing potential (ORP), electrical conductivity (EC), total dissolved solids (TDS), salinity (%), and concentration of arsenic (As) and lead (Pb), respectively. PCA assisted in extracting and recognizing the responsible variation factors of water quality over the region, and the results showed three underlying factors including anthropogenic source pollution along with runoff due to rain and soil erosion were responsible for explaining the 93.87% of total variance. The parameters which were significantly influenced by anthropogenic impact are DO, EC, TDS (negative), and concentration of Pb (positive), while the concentration of As, % salinity, and ORP are affected by erosion and runoff due to rain. The worst pollution situation for regions M1 and M6 was due to the concentration of As which was approximately 400 μg/l (i.e., 40 times higher than minimum WHO recommendation). Furthermore, the results also indicated that, in the Indus River, three monitoring stations and five quality parameters are sufficient to have a reasonable confidence about the quality of water in this most important reserve of Pakistan.