Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent health issues. The improvement of NAFLD is related to the activation of the farnesoid X receptor (FXR). Typhaneoside (TYP) is the main component of Typha orientalis Presl, which plays a positive role in the resistance of glucose and lipid metabolism disorders. This study aims to investigate the alleviative effect and the underlying mechanism of TYP on OAPA-induced cells and high-fat-diet (HFD)-induced mice with disorders of glucose and lipid metabolism, inflammation, oxidative stress and lower thermogenesis through FXR signaling. All the serum lipid, body weight, oxidative stress and inflammatory levels of WT mice were significantly increased after HFD administration. These mice were presented with pathological injury, liver tissue attenuation, energy expenditure, insulin resistance, and impaired glucose tolerance. These above-mentioned changes in HFD-induced mice were remarkably reversed by TYP, which improved HFD-induced energy expenditure, oxidative stress, inflammation, insulin resistance, and lipid accumulation in a dose-dependent manner by activating the expression of FXR. Furthermore, using a high throughput drug screening strategy based on fluorescent reporter genes, we found that TYP functions as a natural agonist of FXR.TYP-mediated FXR activation also significantly repressed TG hyperaccumulation in mouse primary Hepatocytes (MPHs). However, these beneficial effects of TYP were not observed in FXR-/- MPHs. Overall, activation of the FXR pathway by TYP is related to the improvement of metabolic parameters, such as blood glucose, lipid accumulation, insulin resistance, inflammation, oxidative stress and energy expenditure in vitro and in vivo.Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.