One of the main strategies to implement the sustainability of aquaculture is by reducing its dependence on feed raw materials derived from wild marine resources, unsustainable land and freshwater use. To totally replace wild-caught fishmeal (FM), fish oil (FO) and soy protein (SP) in European sea bass, five experimental diets were formulated including increasing levels of fishery and aquaculture by-products (control C, 0FM100FO, 0FM0FO, 0FM0FO-50SP, 0FM0FO-0SP). Diets were administered to triplicate fish groups of 50 individuals reared in a recirculation system for 119 days. No major differences (p > 0.05) between C and 0FM100FO were detected in growth (final body weight) and feed efficiency parameters (feed conversion rate, protein efficiency ratio, gross protein efficiency, lipid efficiency ratio, gross lipid efficiency) while they were reduced (p < 0.05) in 0FM0FO, 0FM0FO-50SP, 0FM0FO-0SP compared to C diet. At the end of the growth trial the overall metabolomic profiles of fish muscle were impacted by the diets. In particular, the increase in glycine and phosphocreatine in the muscle of fish fed with diets containing FM and FO by-products, may suggest changes or adaptation in metabolic pattern for energy production at muscular level; results which were also supported by the higher level in plasma creatinine, uric acid and lactate found in C diets. Concerning welfare indicators, overall plasma parameters were in line with the normal range for this species indicating a general optimal welfare condition under all dietary regimes. No effect of diets on overall gut microbiota layout was observed. However, the inclusion of the FM and FO by-product increase the relative abundance of several taxa such as Weissela, Enterococcus, Streptococcus and Bacillus which could potentially support immune system and disease resistance. Overall this study highlighted the possibility of totally replacing wild-caught FM and FO using by-products from fisheries and aquaculture with an only marginal reduction of the overall performance.