Abstract The present study was conducted to reveal the concentrations and patterns of organochlorines [i.e., organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs)] in freshwater fish species collected from four ecologically important sites of the Indus River i.e., Taunsa (TAU), Rahim Yar Khan (RYK), Guddu (GUD) and Sukkur (SUK). In the fish muscle tissues, concentrations of 15 OCPs (∑15OCPs) and 29 PCBs (∑29PCBs) varied between 1.93–61.9 and 0.81–44.2 ng/g wet weight (ww), respectively. Overall, the rank order of OCs was DDTs > PCBs > hexachlorocyclohexanes (HCHs) > chlordanes (CHLs). The patterns of PCBs showed maximum contribution of tri-CBs (59%). Ratios of individual HCH and DDT analytes contributing to the summed values indicated both recent and past use of these chemicals in the region, depending upon fish species. To assess the associated health risks, carcinogenic and non-carcinogenic risks were calculated through hazard ratios (HRs). For carcinogenic risk, HR was > 1 at both 50th and 95th percentile concentrations, suggesting that the daily exposure to OCPs and PCBs yields a lifetime cancer risk of 1 in a million. HR for non-cancerous risk was < 1 at both the percentiles, signifying no adverse effect by OCs exposure in native population.