This study clarified the significance of including tomato pomace with or without enzymes and/or amino acids in the diet of Nile tilapia on blood parameters, serum biochemicals, antioxidants, and expression of immune- related genes in liver for 8 weeks. Five groups of diet were formulated with protein content (28%): (G1) a control diet without tomato pomace (TP), (G2) TP with 15%, (G3) TP 15% with lysine (1.79%) and methionine (0.94%), (G4) TP 15% with gallizyme (0.2%) and (G5) TP 15% with lysine, methionine and gallizyme. The results of red blood cells (RBCs), white blood cells (WBCs) count and the value of hemoglobin and hematocrit showed non-significant difference in all groups (p>0.05). While, levels of serum creatinine, urea and ALT were significantly decreased in G3, G4 and G5 compared to G2 (P<0.05). There was a significant difference in the levels of serum super-oxide dismutase (SOD), glutathione peroxidase (GPX) and malondialdehyde (MDA) in the last three groups compared to G1 and G2 (P=0.02), (P=0.01), (P<0.0001) respectively. However, phagocytic activity and phagocytic index was non significantly differed in the five groups, but lysozyme activity showed a higher value in G3 and G4 compared to G2 (p<0.05). The relative expression levels of SOD and interleukin-12 in the liver of tilapia were significantly differed (p<0.05) in the last three groups, while expression levels of catalase showed no significant difference in all groups. Finally, inclusion of dietary TP with of enzymes or amino acids could enhance antioxidant status and immune parameters in Nile tilapia fish.