Lake Qarun, a significant water body in Egypt, receives agricultural drainage from the El Fayoum Governorate via several drains, with El-Wadi and El-Bats drains being the primary sources. This study assessed the current water quality of Lake Qarun, heavy metal (HM) concentrations, and pollution indices in both water and the Nile tilapia (Oreochromis niloticus), and the associated human health risks from fish consumption. Based on the Canadian Water Quality Index (CWQI = 47) and the Oregon Water Quality Index (OWQI = 16-38), water quality assessments categorized Lake Qarun as marginal and very poor, respectively. The trophic state index (TSI) ranged from 62.16 to 85.6 throughout the year, indicating poor water quality. Conversely, the Aquatic Toxicity Index suggested that the water remained suitable for fish survival. HM concentrations in the water followed the sequence Fe>Al>Mn>Zn> Pb>Cr> Cu>Ni >Co>Cd. Pollution index (PI) revealed slight pollution by Co, Mn, and Pb in the eastern sector, while Cu exhibited intense pollution near the El-Bats Drain. The HM Pollution Index (HPI) indicated high overall HM pollution in Lake Qarun, potentially posing adverse effects on aquatic organisms. Bioaccumulation factors for HMs in the edible tissue of Oreochromis niloticus were in the sequence of Cd>Ni >Cu> Co > Zn > Mn >Pb> Al > Cr > Fe. Despite individual metal target hazard quotients (THQ) being below the non-hazardous limit (THQ < 1), the Total Hazard Index (HI > 1) revealed a potential health risk to Oreochromis niloticus consumers from the combined effect of heavy metals. This risk was relatively higher in the eastern sector (HI = 1.275) compared to the western sector (HI = 1.148).