The aim of the present study was to evaluate the actual possibility of fish meal substitution in the diet of farmed seabream by poultry by-product meal (PBM) to verify its sustainability in farming practice. Therefore, inclusion of PBM in seabream diet was investigated by a multidisciplinary analysis to evaluate its possible effects on fish growth performances, fish welfare and fillet quality. Thus, control diet (commercial diet) and two experimental diets Feed A and Feed B contained PBM with 50% and 100% of FM substitution respectively were formulated. All diets were isoproteic 45% and isolipidic 20%. The growth trial lasted 110 days including 2 weeks of fish acclimatization. Juveniles gilthead seabream with an initial average weight of 73,57 ± 10,47 g were allotted randomly in 9 tanks (3 replicates per diet), fed once a day by hand (feeding rate 1%). Sampling was performed monthly. As results, average weight gain increased in all fish groups without any statistically significant difference (P>0.05). Measured zootechnical parameters were similar among fish groups, condition factor as an indicator of fish condition was about 2 (good to excellent condition) and survival rate was 100%. Investigations through hematological parameters, digestive enzymes and liver histology analyses demonstrated that no statistical difference was found among dietary treatments and this clear evidence suggest that PBM inclusion in seabream diets did not affect negatively fish welfare. Protein patterns obtained from fish fed with control diet and PBM diets, showed similar expression of structural proteins such as actin, tropomyosin, MLC1, MLC2, MLC3. Results concerning fish fillet compositions were comparable in all fish groups with some exception for fatty acids composition. Gross energy content of seabream muscle was, also, not affected by PBM and resulted value was about 148 Kcal/100g. The present study, demonstrated that the total substitution of fish meal with poultry by product-meal in the commercial diet of gilthead seabream (Sparus aurata) is achievable without compromising fish growth performances, fish welfare and fillet quality and suggests that PBM could be considered as a good sustainable raw material for fish food.