A high-fat (HF) diet alters gut microbiota and promotes obesity related infammation and cognitive impairment. Teasaponin is the major active component of tea, and has been associated with antiinfammatory efects and improved microbiota composition. However, the potential protective efects of teasaponin, against HF diet-induced obesity and its associated alteration of gut microbiota, infammation and cognitive decline have not been studied. In this study, obesity was induced in C57BL/6J male mice by feeding a HF diet for 8 weeks, followed by treatment with oral teasaponin (0.5%) mixed in HF diet for a further 6 weeks. Teasaponin treatment prevented the HF diet-induced recognition memory impairment and improved neuroinfammation, gliosis and brain-derived neurotrophic factor (BDNF) defcits in the hippocampus. Furthermore, teasaponin attenuated the HF diet-induced endotoxemia, pro-infammatory macrophage accumulation in the colon and gut microbiota alterations. Teasaponin also improved glucose tolerance and reduced body weight gain in HF diet-induced obese mice. The behavioral and neurochemical improvements suggest that teasaponin could limit unfavorable gut microbiota alterations and cognitive decline in HF diet-induced obesity.