The current work was designed to assess the effects of waterborne lead and cadmium on biochemical and haematological parameters in Nile tilapia, Oreochromis niloticus, after 60 days of exposure to chronic sub-lethal concentrations. A total of 300 fish individuals of O. niloticus were randomly divided into five treated groups. The first group was the control one. The second (T₁) and third groups (T₂) were exposed to lead (Pb) at concentrations of 0.72 and 3.6 mg/l, respectively. The fourth (T₃) and fifth (T₄) groups were exposed to cadmium (Cd) at concentrations of 0.62 and 3.1 mg/l, respectively. The results of the current study revealed that tilapia fish exposed to lead and cadmium exhibited several behavioural changes, such as anorexia, rapid unbalanced movement, irregular swimming, an increase in operculum movement and slack movement during the experimental duration. The values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine, blood urea and serum total cholesterol showed a highly significant increase in a time-dependent manner in the Pb and Cd exposed groups compared to the control group. While serum albumin was significantly decreased in the Pb and Cd exposure experimental groups. Serum total protein and globulin concentrations showed a non-significant difference among different experiment groups at the end of the experiment period. On the other hand, RBC count, Hb% and Hematocrit levels decreased gradually among exposure time in fish exposed to both low and high concentrations of Pb and Cd. Also, the WBCs count was significantly decreased in fish exposed to Pb and Cd concentrations compared with fish in the control group. The present study indicates that waterborne lead and cadmium exposure have a severe negative impact on Oreochromis niloticus health and these impacts are greater in cadmium than in lead.