The task of this study was to calculate a maximum daily and weekly balanced healthy diet MDI-MWI for human consumption of Clarias gariepinus and Oreochromis niloticus fish species from the Manzalah Lake (Egypt), as well as determine the target cancer/hazard quotient (non–cancer), and risk assessments on human health through physiological and biochemical examinations. the Results showed that the children should not eat more than 13.39g a day or 93.75 g a week of C. gariepinus muscles, and 15.09g a day or 105.63g a week of O. niloticus muscles. The suggested daily intake for youth should be 34.01g or 238.09g a week of C. gariepinus muscles, and 40.24g for daily intake or 281.69g for weekly intake of O. niloticus muscles. Hence, adults are recommended to avoid consuming more than 59.52g a day of C. gariepinus muscle or 416.66g a week and 62.02g a day of O. niloticus muscles or 434.14g a week. This investigation also showed that C. gariepinus had the maximum protein and moisture contents; whereas, the maximum fat, ash, and carbohydrate contents were found in O. niloticus. In this research, the investigated liver antioxidants GPx activity and GSH level represented significant (P < 0.05) average values between both fish species. Moreover, this investigation showed that the C. gariepinus had much greater levels of Pb, As, Al, and Hg than O. niloticus, and the accumulation of elements in both species was in the following order: Pb>As>Al >Hg. Among elements, Pb and Al concentrations in the two fish species recorded analysis of variance revealed a significant difference (P <0.05). In addition, Pb and As concentrations in the two fish species were above the National Egyptian Organization for Standardization and Quality Control EOSQC and international standards FAO, WHO and Commission Regulation EC. Furthermore, this study investigated the estimated daily intake EDI, as well as the estimated weekly intake EWI of Pb > As >Al >Hg ingested by children>youth>adults rely on O. niloticus and C. gariepinus muscles. C. gariepinus in children had the greatest level of target cancer risk TCR (1.01×10^-2 a day or 7.07×10^-2 a week); whereas, O. niloticus in children showed the lowest level of TCR (6.80×10^-6 a day or 4.76×10^-5 a week). Remarkably, the consumers are exposed to health risks if they highly consume the fish species under study from Manzala Lake, according to the health-risk assessment indicators.