This study aimed to evaluate the effects of lysine and histidine supplementation on growth performance, gene expression, blood parameters and quality of the fillet in Nile tilapia, Oreochromis niloticus (n = 192; 136.14 ± 2.32 g). Fish were distributed into four groups and fed a control diet without lysine and histidine supplementation (CON), supplemented with lysine (LYS), histidine (HIS) or lysine and histidine (LYS + HIS) and fed until apparent satiety for 90 days. Growth performance increased significantly in fish fed diet LYS + HIS (p < .05). The fillet body weight gain and fillet yield increased by 26.61% and 2.74% unit, respectively, compared to fish fed CON diet (p < .001). Compared to the control group, fish fed diets showed decreased whole-body lipid and plasmatic triglycerides coupled to increased mRNA levels of MyoD and myogenin in the skeletal muscle and higher texture attributes of fillets (p < .05). There was a substantial negative correlation between body lipids and hardness of fillets. Overall, the combined supplementation of lysine and histidine optimizes growth performance, expression of muscle growth-related genes and flesh quality attributes in grow-out Nile tilapia.