Natural plant or functional food-derived biologically active ingredients have recently raised considerable interest in their antiobesity effect. However, the antiobesity role of polyphenols of white radish roots remains unknown. This study examined the therapeutic efficacy and underlying mechanisms of polyphenols extract from white radish roots (RPE) on obese mice. RPE administration significantly decreased the weight gain in high-fat diet (HFD) fed mouse models. RPE intervention also increased serum glutathione transferase and superoxide dismutase levels, and decreased malondialdehyde, tumor necrosis factor-α and lipopolysaccharide levels in the HFD-fed mice. The intervention led to an escalation in the proportion of beneficial bacteria (Akkermansia, Clostridia), and a corresponding decline in the fraction of harmful bacteria (Proteobacteria). According to liquid chromatography-mass spectrometry-based gut metabolomics, the RPE intervention notably influenced several metabolic pathways, including those involved in protein digestion and absorption, central carbon metabolism related to cancer, and the biosynthesis of steroid hormones. Additionally, RPE treatment led to a reduction in the intestinal microbes possessing bile-salt hydrolase activity, whereas increased the expression levels of the bile acid (BA) synthesis enzyme cholesterol 7α-hydroxylase (Cyp7a1). This led to increase hepatic production and fecal excretion of BAs, reduce hepatic cholesterol, and decrease lipogenesis. Treated HDF-fed mice showed mitigation of hepatic steatosis and inflammation through gut-liver axis modulation by RPE interference. These findings together offer a significant understanding of the potential of RPE as an anti-obesity treatment and could assist in developing strategies for weight loss.