Insulin resistance (IR) is the common basis of diabetes and cardiovascular diseases, and its development is closely associated with lipid metabolism disorder. Flavonoids have definite chemical defense effects, including anti-inflammatory effects, anticancer effects, and antimutation effects. However, the function and mechanism of apigenin (AP, a kind of flavonoid) in IR are still unclear. In our study, intracellular fat accumulation model cells and high-fat diet (HFD)-fed model mice were established using palmitate (PA) and HFD. Mechanistically, we first demonstrated that AP could notably downregulate sterol regulatory element-binding protein 1c (SREBP-1c), sterol regulatory element-binding protein 2 (SREBP-2), fatty acid synthase, stearyl-CoA desaturase 1, and 3-hydroxy-3-methyl-glutaryl-CoA reductase in PA-induced hyperlipidemic cells and mice. Functionally, we verified that AP could markedly reduce lipid accumulation in PA-induced hyperlipidemic cells and decrease the body weight, visceral fat weight, IR, and lipid accumulation in HFD-induced hyperlipidemic mice. Besides, we showed that PA could significantly downregulate endoplasmic reticulum stress (ERS)-related proteins and inhibit ERS. Furthermore, we proved that AP could reduce blood lipids by inhibiting ERS in PA-induced hyperlipidemic cells. Meanwhile, 4-phenyl butyric acid (also called ERS alleviator), like AP, could significantly reduce blood lipids and alleviate IR in HFD-fed model mice. Therefore, we concluded that AP could substantially improve the disorder of lipid metabolism, and its mechanism might be related to the decrease of SREBP-1c, SREBP-2, and downstream genes, the inhibition of ERS, and the reduction of blood lipids and IR. SIGNIFICANCE STATEMENT: Apigenin, a nontoxic and naturally sourced flavonoid, has antihyperlipidemic properties in mice and hepatocyte. This study highlights a new mechanism of apigenin and proposes that these hypolipidemic effects are associated with the mitigation of endoplasmic reticulum stress and insulin resistance in diet-induced obesity. This study might provide translational insight into the prevention and treatment of apigenin in hyperlipidemia-related diseases.