Background <p>After feeding carnivorous mandarin fish (<i>Siniperca chuatsi</i>) with formulated feed, obvious phenotypic differences in body weight and other traits were observed in the fish. Comparative analyses were conducted on the brain tissue transcriptome, intestinal metabolomics, and intestinal microbial diversity of the two groups with body weight differences, aiming to explore whether such differences are associated with individual gene expression levels, metabolic pathways, and intestinal microbiota.</p> Results <p>Compared to the easy-acclimation group (EA), the difficult-acclimation group (DA) exhibited significantly lower body weight and length (<i>P</i> &lt; 0.05). Brain transcriptome analysis identified 1478 differentially expressed genes (DEGs), with key anorexigenic genes <i>mc4r</i>, <i>htr1b</i>, and <i>lgr4</i> significantly upregulated in the DA group. KEGG enrichment analysis showed activation of pathways such as neuroactive ligand-receptor interaction. Metabolomics revealed a significant reduction of six key neuro-nutritional metabolites, including pyridoxine (vitamin B6), L-carnosine, and anserine in the DA group’s gut (|FC| &gt; 5, <i>P</i> &lt; 0.05), indicating impeded metabolic pathways. Correspondingly, the intestinal microbiota of group DA exhibited reduced diversity, dominated by genera such as <i>Clostridium</i>, <i>Latilactobacillus</i>, and <i>Cetobacterium</i>, whereas the EA group was enriched with beneficial genera like <i>Megasphaera</i>, <i>Sanguibacter</i>, and <i>Muribaculum</i>. Furthermore, correlation analysis revealed close associations between brain feeding genes, gut metabolites, and microbiota structure.</p> Conclusion <p>The results of this study indicate that the observed differences in growth performance post-acclimation are associated with the synergistic regulation of brain gene expression, host metabolites, and intestinal microbiota. These results elucidate key molecular mechanisms in the acclimation process of mandarin fish.</p>