<p>To investigate the therapeutic effect of total flavones of <i>Abelmoschus manihot</i> (L.) Medic (TFA) on CCl₄-induced liver fibrosis in mice, and to clarify the mechanism of action of TFA in ameliorating liver fibrosis by untargeted metabolomics and intestinal microbiota 16S rRNA sequencing, in order to provide an experimental basis for the clinical application of TFA in the treatment of liver fibrosis. To establish a mice model of CCl₄-induced liver fibrosis, and liver injury was assessed through histopathology, liver function markers (ALT, AST), inflammatory cytokines, and oxidative stress indicators. Serum untargeted metabolomics was conducted via LC-MS/MS, and intestinal microbiota profiles were analyzed by 16S rRNA sequencing. TFA treatment significantly reduced ALT and AST levels by approximately 55% and 40%, respectively, and markedly ameliorated histopathological changes. It also attenuated oxidative stress and inflammation. Metabolomic analysis identified 83 differential metabolites, indicating that TFA restored disruptions in glycerophospholipid, tryptophan, and arachidonic acid metabolism. Gut microbiota sequencing showed that TFA increased beneficial bacteria and decreased harmful bacteria. Furthermore, TFA downregulated the expression of CYP1A1, CYP2E1, and ALOX15 in liver tissue, suggesting modulation of arachidonic acid metabolism. TFA alleviated CCl₄-induced liver fibrosis in mice by reducing oxidative stress and inflammation, improving gut microbiota dysbiosis, and regulating host metabolism. These findings suggest that TFA may hold potential as a multi-target agent for liver fibrosis, although further studies are required to confirm its efficacy in other models and females.</p>