This study aims to assess the water quality of the Mahananda River in Bangladesh and its suitability for drinking and agricultural uses. For water quality determination, 15 samples were collected from different sites of the Mahananda River to calculate Water Quality Index (WQI) and Entropy Water Quality Index (EWQI). Result shows that among different Hydrochemical parameters, carbonate and bicarbonate concentrations crossed the maximum limit in all the samples, while fluoride concentration exceeding in Sample-15 with the highest value found in Baroghoria area. From WQI result, water quality for the Baroghoria area was found unsuitable for drinking with WQI − 309.22, whereas another two samples of Mollikpur and Namo Neemgachi fall under ‘poor’ category with WQI of 184.49 and 198.99, respectively. EWQI reveals medium to excellent water quality. Result from different irrigation indices (Na%, sodium adsorption ratio (SAR), residual sodium carbonate (RSC), magnesium hazard (MH), total hardness, Kelly ratio (KR), and permeability index (PI) values) showed their suitability for irrigation. Principal component analysis (PCA) explained a total of 89.71% of variances in the dataset. Significant positive association within EC–Na, EC–sulfate, Ca–TH, nitrate–sulfate, etc., were reported indicating prominence in terms of both geogenic as well as anthropogenic processes such as silicate weathering and the release of untreated sewerage, respectively, which governs the water quality evolution in the study area. Cluster analysis (CA) classifies all water samples in five different clusters based on five different characteristics. Mahananda River water is found safe for both drinking and agricultural purposes, except for few samples near the dense human settlement areas. Result from this study is useful for decision makers to design management plans for the river water quality, environmental pollution and human well-being.