The Indus River Basin (IRB) with an area of 139,202 km is the lifeline river basin of Pakistan. An intensive study was conducted in six subcatchments of the IRB with five in the Upper Indus Basin (UIB) and one of the Lower Indus Basin (LIB; between Tarbela Dam and Panjand), i.e., the Gilgit River Basin (UIB-I), Hunza River Basin (UIB-II), UIB-III, UIB-IV and UIB-V, and LIB. A total of 84 surface water samples were collected from main stream and tributaries from June to August, 2016. The pH, electric conductivity (EC), and total dissolved solids (TDS) were measured in situ, whereas major ions (Ca, Mg, K, Na, Cl, SO, and NO) and Si were analyzed in the laboratory. The results exhibited alkaline pH (8.55 ± 0.20) with diverse TDS (114.69 ± 77.65 mg L) and ion concentrations that were characterized primarily by the Ca-Mg-HCO type in the whole basin. The average TDS in the UIB and LIB were 93.99 ± 39.73 and 181.67 ± 167.82 mg L, respectively, under the influence of the arid to semi-arid climatic conditions and relatively higher anthropogenic interference in LIB compared to the UIB. The order of dominant major cations was different in the UIB and LIB, reflecting the diverse nature of geological formation. Gibbs plot, mixing diagrams, and ionic ratios were used to identify the controlling mechanism of river geochemistry in the IRB as carbonate weathering in general with different degrees of silicate weathering and minor contribution by evaporite dissolution. In addition, principal component/factor analysis also indicated that the major sources of dissolved loads in the basin are carbonates followed by silicates. Significant influences of silicate minerals were observed in the LIB, and there was a large contribution of evaporites in the UIB-II, UIB-III, and LIB. The suitability assessment showed that the river water fits the WHO permissible limits for drinking purposes from the perspective of major ions, whereas for irrigation purposes, most of the samples exhibited excellent and good levels except for a couple of permissible and doubtful levels from the Sawan and Deratang tributaries in the LIB, which may deteriorate the quality of soil and degrade the water quality downstream.