Chronic inflammation is involved in the pathogenesis of obesity and type 2 diabetes. Recently, teasaponin, an extract from tea, has been shown to have anti-inflammatory effects. We examined the effect of teasaponin on obesity, inflammation, glucose metabolism and central leptin sensitivity, in obese mice fed a high-fat (HF) diet for 16 weeks. Intraperitoneal injections of teasaponin (10mg/kg, daily) for 21 days significantly decreased the food intake and body weight of HF diet-induced obese mice. Teasaponin treatment also reduced the protein levels of pro-inflammatory cytokines (TNF-α, IL-6 and/or IL-1β) and NF-κB signaling (p-IKK and p-IκBα) in adipose tissue and the liver. The anti-inflammatory effects of teasaponin were associated with improved glycemic status in the treated animals, evidenced by improved glucose tolerance, homeostasis model assessment (HOMA) and fasting plasma insulin. In the hypothalamus teasaponin decreased both pro-inflammatory cytokines and inflammatory signaling in the mediobasal hypothalamus. Teasaponin treatment also enhanced the anorexigenic effect of central leptin administration, restored leptin p-STAT3 signaling in the Arc, and increased hypothalamic expression of the anorexigenic peptide proopiomelanocortin (POMC). These results identify a potential novel application for teasaponin as an anti-obesity and anti-inflammatory agent.