A fifteen-week growth trial was conducted to investigate the effect of reducing dietary protein levels in Nile tilapia (Oreochromis niloticus) with dietary supplementation of commercially available synthetic amino acids at different levels (100 and 120% NRC, 1993) on growth performance, whole-body composition, morphometric indices, serum metabolites, immune and antioxidant biomarkers. The experiment consisted of six isoenergetic (3000 Kcal DE/Kg) dietary treatments with two replications per each. The first four groups of diets were formulated to contain different levels of dietary protein (32, 30, 28, and 26%) in which the indispensable amino acid (IAA) profile covered the IAA requirements for Nile tilapia as recommended by the NRC (1993), except for the low protein diet (26%) in which methionine was supplemented. The last two groups of diets were formulated to contain 26 and 28% crude protein in which IAAs were adjusted to be 120 % of the NRC requirements. By reducing dietary protein levels to 26%/IAA/100%NRC, final body weight (FBW), weight gain (WG), weight gain percent (WG %), specific growth rate (SGR), protein efficiency ratio (PER), and feed intake (FI) were significantly reduced, while feed conversion ratio (FCR) was significantly increased. Indispensable amino acid supplementation at 120% of the NRC requirements to low protein diets (26 and 28%) resulted in a significant improvement in all growth performance parameters. Reducing dietary protein with IAA supplementation did not affect whole-body moisture and crude protein, while fat and ash content were significantly increased. Serum total protein (TP), albumin (ALB), glucose, and serum superoxide dismutase (SOD) activity were not significantly altered by lowering dietary protein levels to 26%, while serum triglycerides (TG), cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, and creatinine concentrations showed a significant increase. Serum IgG, IgM, and reduced glutathione (GSH) showed a significant improvement with IAA supplementation at 120% of the NRC requirements to 26 and 28% protein diets. In conclusion, dietary protein level could be lowered to 26% in Nile tilapia diets with supplementation of IAA at 120 % of the NRC requirements while maintaining comparable growth performance, feed utilization, immune and antioxidative responses.