River Hooghly, a tributary of river Ganges is one of the major rivers of Asia having traditional, social, economic, religious, and spiritual values. Water samples were collected from 18 sampling locations of river Hooghly during summer (dry), monsoon (wet), and winter (cold) seasons. The samples are analysed for basic physicochemical properties and abundance of selected potentially toxic elements (PTEs) are measured. Several PTEs, e.g., Al, Fe, Ni, and Pb, were found to be above the permissible limits, prescribed by national and international guidelines for safe human consumption. The trend of variation in the mean PTE concentrations showed the following order: Cd < Pb < Co < Cr < Ni < Cu < Zn < Mn < Fe. Due to the presence of high total dissolve solid (TDS) and PTE contents, the water quality of river Hooghly is not suitable for direct human consumption. The evaluated Water Quality Index (WQI) value showed a distinct spatio-temporal variation indicating very severe condition of water quality, which is deteriorating gradually from upstream to downstream. In summer, monsoon, and winter, the highest WQI values were observed in Maushuni Island (S15), Petuaghat (S18), and Tapoban (S17), respectively. However, the non-carcinogenic human health risk in terms of Hazard Quotient and Hazard Index values of PTEs indicates no immediate adverse impact on human health due to exposure of PTE contaminated water from river Hooghly through ingestion or dermal route. Though, these risk values for children were higher than adults warranting the adoption of a long-term management plan to cope with potential human health risks. The result suggests implementation of a combination of stringent socio-legal regulations and numerical models for sustainable water related health risk management in river Hooghly. © 2021, The Author(s).