The aim of the present study was to assess the hematological alterations induced by Zn and Cd individually or in combination in Nile tilapia (Oreochromis niloticus). Fish were exposed to 0.5 and 5.0 mg/L Zn, 0.1 and 1.0 mg/L Cd, and 0.5 mg/L Zn + 0.1 mg/L Cd and 5.0 mg/L Zn + 1.0 mg/L Cd mixtures for 7 and 28 days. Significant changes in all hematological parameters were found to be either dose or time dependent. The exposure of O. niloticus to metals resulted in decreases in red blood cell, hemoglobin, hematocrit, and white blood cell, which shows the anemic state of the fish and the weakening of the immune system. Our work showed that hematological parameters are sensitive indicators to monitor physiological and pathological changes induced by metals.