A growth trial was conducted to evaluate the effect of dietary plant-protein replacement by corn distillers dried grains with solubles (DDGS), and of exogenous carbohydrases supplement (Natugrain®TS, BASF) in gilthead seabream (Sparus aurata) juveniles. For that purpose, a basal diet was formulated with 35% of fish meal and 20% soybean meal (SBM) as main protein sources. Two other diets were formulated incorporating 15 or 35% of DDGS, replacing 37.5% or 100% of SBM (diets DDGS15 and DDGS35, respectively). Another diet was formulated similar to diet DDGS35 and supplemented with 0.1% of a commercial non-starch polysaccharidases complex, Natugrain®TS, BASF (CHOase; diet DDGS35ENZ). Triplicate groups of fish (IBW = 15 ± 1 g) were fed the experimental diets for 67 days at 22 °C. At the end of the trial, growth performance, voluntary feed intake, feed efficiency, protein and energy retention were not affected by dietary DDGS incorporation. Dietary CHOase supplementation also did not affect growth performance, but increased feed efficiency, nitrogen and energy retention. Dietary inclusion of DDGS tended to decrease production cost (€ per kg of fish), and dietary CHOase supplementation further reduced production cost, which was significantly lower with diet DDGS35ENZ than with the basal diet. Whole-body composition, hepatosomatic and visceral indexes were not affected by the dietary inclusion of DDGS, though a trend was noticed for a decrease of whole-body lipid, energy, and visceral index with the increase dietary DDGS. Plasma glucose, protein, albumin, and globulins levels were similar among diets, whereas plasma triglycerides increased, and cholesterol decreased with the increase of dietary DDGS. Hepatic glycolytic enzymes activities (hexokinase and glucokinase) were similar among groups, while gluconeogenic (fructose biphosphatase) activity, GDH and ASAT activities decreased with the increase of dietary DDGS. The hepatic activity of oxidative stress-related enzymes catalase and superoxide dismutase were not affected by dietary treatments, but G6PDH and GR activities decreased, and liver lipid peroxidation increased with dietary DDGS level. Dietary CHOase supplementation decreased overall lipid peroxidation.Overall, results of this study indicate that total replacement of SBM by DDGS in diets for gilthead seabream did not compromise growth performance or feed utilization efficiency, while supplementation of DDGS-based diet with exogenous carbohydrases improved feed utilization efficiency and economic efficiency ratio.