Blueberry leaf polyphenols (BLP) have shown therapeutic potential against obesity-related metabolic syndromes. However, the sexually dimorphic mechanisms underlying these effects remain underexplored. Our study demonstrates significant sex-dependent effects of BLP in ameliorating HFD-induced obesity in mice. Specifically, BLP administration resulted in a more pronounced reduction in body weight and hepatic steatosis in male mice, while it induced a more substantial decrease in subcutaneous white adipose tissue mass in females. Integrated network pharmacology and molecular validation further demonstrated that the anti-obesity effect of BLP was predominantly mediated through activation of the AMPK/PGC-1α/ERRα pathway to enhance fatty acid oxidation in male mice. Conversely, in female mice, the effect was primarily achieved through suppression of the PPAR-γ/SREBP-1/FAS pathway, thereby reducing lipid synthesis. Integrated multi-omics analysis revealed that in obese male mice, BLP intervention significantly enriched beneficial gut microbes such as Akkermansiaceae and Oscillibacter, which subsequently elevated levels of metabolites including palmitic acid, linoelaidyl carnitine, and LysoPC (18:0). These changes collectively promoted fatty acid oxidation, accelerated hepatic lipid consumption, and ameliorated lipid accumulation-induced liver injury and hepatomegaly. In contrast, that in obese female mice, BLP intervention significantly increased abundances of Lactobacillus, Bifidobacterium, and Enterorhabdus, along with elevated expression of arachidonic acid, FAD, and LysoPC (16:0). This microbial and metabolic profile ultimately suppressed lipogenesis, significantly reduced adipocyte size, and effectively attenuated HFD-induced subcutaneous white adipose tissue accumulation. These multi-level interactions collectively drive hepatic lipid clearance in males and adipose remodeling in females, establishing a "microbiome-metabolite-signaling-host" axis that underpins BLP's sex-specific therapeutic efficacy against obesity.