During the last three decades, an annual proliferation in the levels of heavy metals was detected in the River Nile due to sewage, industrial and agricultural wastewater discharged into the river waters. Thus, the current study was set with the aim of investigating the possible health risks associated with water use and the consumption of Oreochromis niloticus via comparing and determining various exposure pathways and potential health risks corresponding with heavy metals in surface water and fish off the River Nile using a number of indices. S1: El-Qanater El-Khayria site (S1; reference clean site) prior to the bifurcation, S2: El-Rahawy drain discharge point into the Rosetta Branch, and S3: El-Qatta site (about 7 km from S2) were the three locations covered by the present investigation throughout winter and summer of 2023. Heavy metals' levels were addressed (Fe, Cr, Cd, Zn, and Cu).  Among the metals under research, Fe had the highest concentration, followed by Zn> Cu> Cr> Cd, and S2 had the highest heavy metal load over the course of the study. In contrast to the FAO guidelines for irrigation water and the USEPA guidelines for drinking water, water samples from S1 of the River Nile were suitable for both uses during the study, despite the fact that the heavy metal evaluation index (HMEI) of water samples taken from S2 and S3 of the Nile indicated that both sites are unsuitable for irrigation and drinking. O. niloticus off site S3 was monitored for non-carcinogenic health concerns in accordance with USEPA recommendations. However, chromium in fish at S3 exhibited higher lifetime potency of cocarcinogenic risks, particularly for habitual consumers. The current findings confirm the necessity of rapid water quality management planning, especially in heavily polluted areas, to secure safe water usage and maintain ecological balance and human well-being. These results also emphasize the importance of understanding the site-specific cancerogenic risks related to exposure to heavy metals in different locations and consumption patterns to appraise aquatic food safety and health risk assessments.