As aquaculture expands, replacing fishmeal with alternative proteins in low-trophic species such as Chelon labrosus is critical for sustainability. We evaluated growth performance over 153 days and nutrient digestibility of three isoproteic diets: a fully plant-based diet (V), a plant–animal blend without fishmeal (VA), and a control with 20% fishmeal (FM). Fish fed the V diet achieved the highest growth and feed efficiency, followed by FM, whereas VA resulted in poor performance and the lowest digestibility, likely linked to hemoglobin meal reducing feed acceptability. All diets significantly shifted intestinal microbial diversity from initial conditions, while dominant taxa remained largely stable. FM-fed fish showed a general decrease in bacterial abundance, including a marked reduction of Brevinema. The VA diet increased Vibrio and decreased Lactobacillus, suggesting compromised gut health. In contrast, V-fed fish displayed elevated Mycoplasma, a taxon previously associated with nutrient exchange and fiber digestion. Functional predictions indicated fewer metabolic alterations under plant-based diets, while FM induced the largest number of altered pathways. Overall, complete fishmeal replacement is feasible in C. labrosus, and diet–microbiome interactions are pivotal to optimizing sustainable mullet aquaculture., Ministerio de ciencia e investigación. Programa "Think In Azul”. European Union Next Generation-Plan. Gobierno de Cantabria.