Obesity pathogenesis involves a multifaceted interplay between systemic metabolic dysregulation and intestinal microbiota dysbiosis. Using a high-fat diet (HFD)-induced obese mouse model, this research aimed to elucidate the anti-obesity effects and metabolic regulatory functions of Hericium erinaceus polysaccharides (HEP). HEP markedly attenuated weight gain and intrahepatic fat deposition, while enhancing systemic glucose disposal and insulin sensitivity. These metabolic improvements were closely associated with modulation of the hepatic AMPK/SREBP-1c signaling pathway, which downregulated lipogenic genes (FAS, ACC, and SREBP-1c) and enhanced lipid catabolism. The reduced metabolic stress subsequently promoted the organization of epithelial intercellular junctions, as demonstrated by the up-regulation of key barrier proteins, including Occludin, Claudin-1, and ZO-1 and the suppression of TLR4/NF-κB-mediated inflammatory cascades. Notably, HEP treatment remodeled the intestinal microbial landscape by fostering the enrichment of advantageous genera (e.g., Ileibacterium) and suppressing obesity-related bacteria (e.g., Lachnoclostridium). These findings suggested that HEP alleviated obesity by orchestrating a “metabolism-inflammation-microbiota” signaling axis, thereby positioning it as a feasible dietary intervention for the prevention and treatment of obesity.