This work aimed to assess residues of   some heavy metal in Tilapia fish (Oreochromis niloticus) of varying weights captured from El Temsah Lake in Ismailia City, as well as evaluating their potential impacts on serum biochemical parameters, antioxidant state of liver and nutritional values of fish meat. One hundred random samples of Tilapia fish were collected in total (distributed into 3 different body weights groups) and were analyzed. The results displayed the presence of some heavy metal residues as lead, cadmium and copper in meat and liver, and their concentrations were directly correlated with fish size as residues were found to be higher in the larger Tilapia compared to the smaller ones. Regarding Egyptian (No. 7136/2010) and European Commission (EC, 2006), and FAO/WHO (2002), 12% and 8% of total meat samples exceeded the permissible limits of lead and cadmium, respectively. While all samples of meat were within the permissible limit of copper concentration. In large sized fish, heavy metal residues led to significant rise in the levels of serum alanine and aspartate aminotransferases, creatinine, uric acid, indicating hepatic and renal dysfunction. Moreover, the activity of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), in large sized Tilapia fish exhibited an increase. However, the proximate analysis of the examined tilapia meat showed that the heavy metals concentrations in meat were not high at a level that affected the nutritive values of fish meat. Totally, significant efforts and coordination among various authorities are required for treating sewage, industrial and agricultural wastes. It is also crucial to regularly check for toxic residues in fish.