Scope Obesity has become a major health problem worldwide and is associated with low‐grade chronic inflammation and intestinal dysbiosis. This study is conducted to investigate the chemopreventive effects of garcinol, a polyisoprenylated benzophenone derivative isolated from the fruit rind of Garcinia indica. How garcinol protects against obesity in high‐fat diet (HFD)‐induced mice is delineated and whether its anti‐obesity effects are related to gut microbiota has been determined. Methods and results The results show that garcinol reduces HFD‐fed mice body weight gain and relative visceral adipose tissue fat weight in a dose‐dependent manner. Furthermore, garcinol markedly reduces the plasma levels of glutamate pyruvate transaminase, total cholesterol, and triacylglycerol. The 16S rRNA gene sequence data indicate that garcinol not only reverses HFD‐induced gut dysbiosis—as indicated by the decreased Firmicutes‐to‐Bacteroidetes ratios—but also controls inflammation by increasing the intestinal commensal bacteria, Akkermansia. In addition, the AMP‐activated protein kinase α signaling pathway involved in adipocyte adipogenesis is also affected by garcinol. Conclusion Taken together, these results demonstrate for the first time that garcinol can prevent HFD‐induced obesity and may be used as a novel gut microbiota modulator to prevent HFD‐induced gut dysbiosis and obesity‐related metabolic disorders.