Obesity is an important and preventable risk factor for renal disease. The administration of an antioxidant with a lipid-lowering effect is an important therapeutic approach for kidney disease in obese patients. The present study was conducted to examine whether methanolic extract of Dendrobium moniliforme (DM), one of the most famous traditional medicines used in many parts of the world, has an antioxidant effect in vitro and an ameliorative effect on high-fat diet (HFD)-induced alterations such as renal dysfunction and lipid accumulation in vivo. The 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity of DM extract (IC(50) = 29.6 μg/mL) was increased in a dose-dependent manner. The LLC-PK1 kidney cell damage induced by oxidative stress was significantly inhibited by the treatments with DM extract. In the animal study, DM extract (200 mg/kg) was orally administered every day for nine weeks to HFD-fed mice, and its effect was compared with that of metformin. The administration of DM extract decreased the elevated serum glucose, total cholesterol concentration and renal lipid accumulation in HFD-fed mice. It also ameliorated renal dysfunction biomarkers including serum creatinine and renal collagen IV deposition. Taken together, these results provide important evidence that DM extract exhibits a pleiotropic effect on obesity induced parameters and exerted a renoprotective effect in HFD-fed mice.