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The experiment investigated the effect of dietary orange pulp (OP) with or without enzymes supplementation on the performance parameters, chemical composition, serum biochemistry, and some liver gene expression in tilapia for twelve weeks. The studied fish (n = 300) were allotted into six groups according to OP level (0%, 10%, and 20%) with or without enzymes supplementation (+/-). The performance results indicated that the inclusion level of OP by 20% negatively affected FCR and decreased final body weight. The dietary enzymes did not alleviate the unfavorable effect of OP on the final body weight. Higher dietary replacement levels of OP reduced serum lipid profile, serum proteins, and carcass fat, but increased carcass protein and ash compared to the control. The dietary enzymes produced higher serum lipids and proteins as compared to non-supplemented groups. Fish-fed the control diet supplemented with enzymes (G2) expressed higher RNA levels of GHR and IGF1 genes compared to the other groups. Excess dietary OP lowered the RNA level of FAS and LPL genes but improved simultaneously when supplemented with enzymes. Overall, the higher dietary OP (20%) with or without enzymes supplementation, did not benefit the tilapia performance, metabolic, and genetic indices, and the chemical composition of the carcass. But, the lower level of OP (10%) supplemented with enzymes could be used in tilapia diets without adverse effects on performance, health, and carcass composition.