<p>High-carbohydrate aquafeeds can induce metabolic disorders and growth inhibition in fish. This study aimed to investigate the beneficial effects of sodium acetate supplementation to a high-carbohydrate diet on grass carp (<i>Ctenopharyngodon idella</i>) and the related molecular mechanisms. Three isonitrogenous and isolipidic diets, including MC (27.5% carbohydrate), HC (42.5% carbohydrate), and HCA (42.5% carbohydrate + 1800 mg/kg sodium acetate), were fed to grass carp until apparent satiation for 7 weeks. The chemical composition, plasma parameters, the expression of genes related to appetite and glucose/lipid metabolism, and the AMPK signaling pathway were evaluated. The results showed that the HC diet upregulated appetite-suppression genes (<i>pomc</i>, pro-opiomelanocortin; <i>cart</i>, cocaine–amphetamine-regulated transcript) and reduced feed intake compared to the MC group. Indicators of glucose and lipid metabolic disorder increased significantly, suggesting the development of fatty liver. These alterations might contribute to poor growth. Sodium acetate supplementation in the HC diet restored feed intake and weight gain, along with downregulation of <i>pomc</i>. Furthermore, the HCA group showed reduced systemic and hepatic lipid deposition compared to the HC group. Mechanistically, sodium acetate enhanced AMP-activated protein kinase (AMPK) phosphorylation and downregulated key lipogenic genes (<i>srebp1</i>, sterol regulatory element-binding protein 1; <i>acc1</i>, acetyl-CoA carboxylase 1; <i>fas</i>, fatty acid synthase). In conclusion, dietary sodium acetate attenuated the adverse effects of the high-carbohydrate diet, potentially by modulating the AMPK/SREBP1 pathway to suppress lipid synthesis and by improving appetite regulation.</p>