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<div><p>Sarmentosin (SA) and Quercetin (QC) are two active components of <i>Sedum Sarmentosum</i> Bunge, which is a traditional Chinese herbal medicine. This study aimed to investigate the role and regulatory mechanism of SA and QC in fatty liver of Genetic Improvement of Farmed Tilapia (GIFT) tilapia. GIFT tilapia were randomly divided into two groups with three replicates per treatment (30 fish in each replicate): normal diet group (average weight 3.51±0.31 g) and high-fat diet group (average weight 3.44±0.09 g). After 8 weeks feeding trial, growth index, lipid deposition, and biochemical indexes were measured. Lipid deposition, and lipid and inflammation-related gene expression were detected in a primary hepatocyte model of fatty liver of GIFT tilapia treated with SA or QC. Our results showed that high-fat diet caused lipid deposition and peroxidative damage in the liver of GIFT tilapia. The cell counting kit-8 assay results indicated that 10 μM SA and 10 μM of QC both had the least effect on hepatocyte proliferation. Moreover, both 10 μM of SA and 10 μM of QC showed lipolytic effects and inhibited the expression of lipid-related genes (<i>FAS</i>, <i>Leptin</i>, <i>SREBP-1c</i>, and <i>SREBP2</i>) in fatty liver cells. Interestingly, QC induced autophagosome-like subcellular structure and increased the expression of <i>IL-8</i> in fatty liver cells. In conclusion, this study confirmed that SA and QC improved fatty liver caused by high-fat diet, providing a novel therapeutic approach for fatty liver of GIFT tilapia.</p></div>