ABSTRACT: Rheum palmatum L. is a traditional Chinese medicine with various pharmacological properties, including anti-inflammatory, antibacterial, and detoxification effects. In this study, the mechanism of the hypoglycemic effect of purified anthraquinone-Glycoside from Rheum palmatum L. (PAGR) in streptozotocin (STZ) and high-fat diet induced type 2 diabetes mellitus (T2DM) in rats was investigated. The rats were randomly divided into normal (NC), T2DM, metformin (Met), low, middle (Mid), and high (Hig) does of PAGR groups. After six weeks of continuous administration of PAGR, the serum indices and tissue protein expression were determined, and the pathological changes in liver, kidney, and pancreas tissues were observed. The results showed that compared with the type 2 diabetes mellitus group, the fasting blood glucose (FBG), total cholesterol (TC), and triglyceride (TG) levels in the serum of rats in the PAGR treatment groups were significantly decreased, while superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) levels were noticeably increased. The expression of Fas ligand (FasL), cytochrome C (Cyt-c), and caspase-3 in pancreatic tissue was obviously decreased, and the pathological damage to the liver, kidney, and pancreas was improved. These indicate that PAGR can reduce oxidative stress in rats with diabetes mellitus by improving blood lipid metabolism and enhancing their antioxidant capacity, thereby regulating the mitochondrial apoptotic pathway to inhibit?-cell apoptosis and improve ?-cell function. Furthermore, it can regulate Fas/FasL-mediated apoptosis signaling pathway to inhibit ?-cell apoptosis, thereby lowering blood glucose levels and improving T2DM.