We report a comparison of tissue-specific (head kidney, intestine and liver) gene expression profiles from gilthead sea bream fed with control and Brewer's spent dry yeast (SDY) diets.The inclusion of SDY at 30% in the experimental diet (40% crude protein, 16% crude lipid) resulted in a reduction in FM (10%) and PP (31.4%) contents. 218 differentially expressed genes (DEGs) were identified among all tissues, out of which, 141 were up- and 77 down-regulated. The enrichment analysis of DEGs revealed that SDY had a modulatory effect on several processes related to host’s immunity, oxygen’s carrier capacity, sexual differentiation, metabolism, and digestion. This study supports the notion that brewery’s by-products like SDY are suitable for aquafeeds of carnivorous fish species such as the gilthead sea bream, and promotes a circular bioeconomy model that reuses, recovers and recycles resources instead of producing wastes Overall design: Gene expression analysis in head kidney, intestine and liver using RNA-seq, between gilthead sea bream group fed a control diet and an experimental Brewer's spent dry yeast (SDY) diet at 30% inclusion, replacing 10% fish meal and 31.4% plant proteins.