This study aims to elucidate the mechanism by which allicin modulates lipid metabolism in HFD (High-Fat Diet) mice through the CSE/H2S pathway. Allicin intervention (120 mg/kg) significantly reduced mouse body weight and serum total cholesterol (TC) and triglyceride (TG) levels (p < 0.05), while enhancing hepatic antioxidant levels (p < 0.05). Transcriptomic analysis of the liver indicated that allicin influenced several key metabolic pathways, including lipid metabolism (steroid hormone synthesis, unsaturated fatty acid synthesis, and PPAR signaling pathways) and antioxidant pathways (chemical carcinogenesis-reactive oxygen species pathway and glutathione metabolism pathways). RT-qPCR experiments confirmed that in the HA group (the high dose allicin, 120 mg/kg), the expression level of CD36 in the liver was downregulated, while the expression of LPL, GST, GPX, and GCLC were upregulated. Furthermore, the metabonomic analysis identified core differential metabolites primarily associated with sulfate/sulfite metabolism and glutathione metabolism pathway. This was evidenced by alterations in the levels of sulfur-containing compounds, such as H2S, l-Glutathione (reduced), G-glutamylcysteine, and methionine. In the constructed HepG2 high-fat cell model, dl-Propargylglycine (PAG, H2S synthesis inhibitor) treatment resulted in significantly higher lipid content compared to the Allicin-600 group, and expression levels of antioxidant genes like GST, GPX, and GCLC are reduced. This further validates the pivotal role of the CSE/H2S pathway in allicin's lipid-lowering effects. In summary, allicin demonstrates potent lipid-lowering activity when serving as an H2S donor, setting the stage for the development of a broader range of allicin-related health products.