Obesity and associated comorbidities are closely linked to gut microbiota dysbiosis, energy balance, and chronic inflammation. Tangeretin, a key citrus polymethoxylated flavone (PMF), is abundant in citrus fruits and has preventative and therapeutic effects for numerous diseases. The current study investigated the effects and possible mechanisms of tangeretin supplementation in preventing obesity in high-fat diet (HFD)-fed mice. Treatment of HFD-fed mice with tangeretin potently ameliorated HFD-induced body weight, liver steatosis, glucose intolerance, and insulin resistance. Tangeretin mitigated systemic chronic inflammation by reducing metabolic endotoxemia and inflammation-related gene expression in HFD-fed mice. An increased number of small brown adipocytes possessing multilocular and cytoplasmic lipid droplets and upregulation of thermogenic gene expression were observed after tangeretin treatment. 16S rRNA amplicon sequencing indicated that tangeretin markedly altered the gut microbiota composition (richness and diversity) and reversed 16 operational taxonomic units (OTUs) back to levels seen in mice consuming a normal chow diet (NCD). Notably, tangeretin decreased the ratio of Firmicutes-to-Bacteroidetes and greatly enriched Bacteroides and Lactobacillus. Overall, our results suggest that long-term supplementation with citrus tangeretin ameliorates the phenotype of obesity by improving adipose thermogenesis and reducing systemic inflammation and gut microbiota dysbiosis, which provides a good basis for studying the mechanism of tangeretin's beneficial effects.