Large amounts of potentially toxic elements (PTEs) have, and continue to be, released into the freshwater ecosystems of Pakistan. However, there is limited information available on the ecological risk of PTEs from sediments and fish consumption, for both the general population and fishermen, at the national scale in Pakistan. In this study, water, sediments and fish samples were collected from major rivers (Chenab, Upper Indus, Lower Indus and Kabul) across Pakistan and analyzed through Inductively Coupled Plasma Mass Spectrometer (ICP–MS), Inductively Coupled Plasma Atomic Emission Spectroscopy ICP–AES and Atomic Fluorescence Spectrometry (AFS), respectively. Ecological risk analysis of sediments revealed that Cd posed a high ecological risk in the Upper Indus and Chenab, a considerable risk in the Lower Indus, and moderate risk in the Kabul. The target hazard quotient of As through fish tissue consumption exceeded safety levels for fishermen at all the rivers, where Cd exceeded at Upper Indus and Chenab, and Pb for Chenab fishermen only. For the general population, PTE ingestion through fish tissues was within the safety limits at all rivers. Meanwhile, the total target hazard quotient in all three rivers exceeded the safety limit, representing a high risk for the fishermen of Pakistan. The results show that ecological risk and target hazard quotient assessment not only provides valuable information for future research in terms of PTE contamination in the major rivers of Pakistan, but also all the metal pollutants from rivers finally reach to Arabian Sea, therefore might pose a risk to marine ecosystem at national and international scale. Display omitted •Water, sediments and fish of Chenab, Indus and Kabul rivers analyzed for toxic metals.•Ecological risk of PTEs from sediments and fish consumption was assessed.•The ecological risk index of Cd and As was higher than other elements.•Hazard quotient of As and Cd via fish ingestion exceeded safety levels for fishermen.•Total target hazard quotient also exceeded safety limits for fishermen in all the rivers.