Within the modern aquaculture goals, the present study aimed to couple sustainable aquafeed formulation and culturing systems. Two experimental diets characterized by 3 and 20% of fish meal replacement with full-fat spirulina-enriched black soldier fly (Hermetia illucens) prepupae meal (HPM3 and HPM20, respectively) were tested on European seabass (Dicentrarchus labrax) juveniles during a 90-day feeding trial performed in aquaponic systems. The experimental diets ensured 100% survival and proper zootechnical performance. No behavioral alterations were evidenced in fish. Histological and molecular analyses did not reveal structural alterations and signs of inflammation at the intestinal level, highlighting the beneficial role on gut health of bioactive molecules typical of HPM or derived from the enriching procedure of insects’ growth substrate with spirulina. Considering the quality traits, the tested experimental diets did not negatively alter the fillet’s fatty acid profile and did not compromise the fillet’s physical features. In addition, the results highlighted a possible role of spirulina-enriched HPM in preserving the fillet from lipid oxidation. Taken together, these results corroborate the use of sustainable ingredients (spirulina-enriched HPM) in aquaponic systems for euryhaline fish rearing.