Lake Qaroun, one of Egypt's largest lakes, is a remnant of a much larger one; it is considered as a closed basin used as a general reservoir for agricultural wastewater drainage in El-Fayoum Province. Furthermore, the lake receives agricultural and partially treated sewage water from the El-Fayoum Governorate as well as fish farm drainage. The current study assessed the changes in physicochemical characteristics and heavy metal levels (Zn, Pb, Cd, and Cu) in water and sediment, as well as the bioaccumulation of these heavy metals in Mugilcephalus fish samples obtained from Lake Qaroun. Thus, information on histopathological changes in the gills, liver, kidney, end of the alimentary canal, and muscles was provided. This research was conducted in three different locations along Lake Qaroun (Eastern, southeastern, and western). This study confirms an increased heavy metal pollution in the eastern and southeastern sectors of Lake Qaroun, facing the drain outlet, as a result of the discharge of drainage water effluents without prior treatment, which directly affects water quality and fish health, and subsequently human health. The concentrations of Pb and Cd in the water exceeded the allowable limits. The gills are the target organ for Cd in Mugil cephalus, but Pb and Zn are preferentially collected in the kidneys, with the liver containing the highest concentrations of Cu ions. Histopathological changes with an evident damage were visible in the gills, liver, and kidneys of Mugil cephalus taken from the lake's eastern and southeastern areas. In addition, blood parameters of Mugil cephalus collected from various study sites throughout Lake Qaroun were included in this study. A highly significant decrease was detected in red blood cell counts, hemoglobin content, and hematocrit values of fish collected from the lake's eastern and southeastern parts in comparison to fish collected from the western sector, indicating more or less normal values.