Exocarpium Citri Grandis (ECG; Huajuhong in Chinese) is a precious traditional Chinese medicine with a history of hundreds of years in China. It has been demonstrated to possess numerous pharmacological properties, including antitussive, expectorant, anti-inflammatory, hypoglycemic, and hypolipidemic. However, no in-depth report exists on the hypoglycemic and hypolipidemic properties of ECG. This study aimed to evaluate the hypoglycemic and hypolipidemic properties of ECG flavonoids extract in vitro and in vivo so as to lay the foundation for further researches in this field. Total flavonoids (TF) and naringin were separately extracted from ECG, and the components of TF were identified by HPLC-MS. The antioxidant capacities of TF and naringin were determined by 2,2,1-diphenyl-1-picrylhydrazyl (DPPH)-free radical scavenging tests, and digestive enzymes activity inhibition assays in vitro in order to evaluate their hypoglycemic properties. Furthermore, diabetic mice experiments were performed to assess the hypoglycemic and hypolipidemic properties of TF and naringin in vivo. Five compounds were identified from TF, including naringin, rhoifolin, poncirin, bergaptol, and naringenin. The half maximal inhibitory concentration (IC50) of TF and naringin to DPPH-free radicals were 0.269 and 1.946 mg/mL, respectively. TF and naringin demonstrated a certain inhibitory effect on α-glucosidase and a weaker inhibitory effect on α-amylase. The results of animal experiments showed that TF and naringin had no significant effect on the blood glucose levels, but they could lead to significant (p < 0.05 or p < 0.01) increase in the serum insulin level and high-density lipoprotein cholesterol (HDL-C) levels with concomitant reduction in the total cholesterol (TC), total triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) levels in diabetic mice. In addition, TF and naringin could reduce the liver index of diabetic mice (p < 0.01) and reduce the kidney index at low doses (p < 0.05). Our study revealed that the hypoglycemic and hypolipidemic activities of TF is mainly derived from naringin, and other active ingredients in TF also have the effects of alleviating oxidative stress, inhibiting digestive enzyme activity and reducing blood lipids. Our results thus provide a scientific basis for the application of ECG in antidiabetic treatment. Copyright © 2020 Elsevier B.V. All rights reserved.