Background and Aims: The pathogenesis of liver fibrosis involves liver damage, inflammation, oxidative stress, and intestinal dysfunction. Indole-3-propionic acid (IPA) has been demonstrated to have antioxidant, anti-inflammatory and anticancer activities, and a role in maintaining gut ho-meostasis. The current study aimed to investigate the role of IPA in carbon tetrachloride (CCl4)-induced liver fibrosis and explore the underlying mechanisms. Methods: The liver fi-brosis model was established in male C57BL/6 mice by in-traperitoneal injection of CCl4 twice weekly. IPA intervention was made orally (20 mg/kg daily). The degree of liver injury and fibrosis were assessed by serum alanine aminotrans-ferase (ALT), aspartate aminotransferase (AST), and histo-pathology. Enzyme-linked immunosorbent assay and quanti-tative real-time polymerase chain reaction (qPCR) were used to detect the inflammatory cytokines. The malondialdehyde (MDA), glutathione, glutathione peroxidase, superoxide dis-mutase, and catalase were determined via commercial kits. Hepatocyte apoptosis was detected by terminal deoxynu-cleotidyl transferase-mediated dUTP nick end labeling assay. The expression of mRNA and protein was assayed by qPCR, Western blotting, or immunohistochemical staining. Results: After IPA treatment, the ALT and AST, apoptotic cells, and pro-inflammatory factor levels were enhanced significantly. Moreover, IPA intervention up-regulated the expression of collagen I, α-smooth muscle actin, tissue inhibitor of matrix metalloproteinase-1, matrix metalloproteinase-2, transform-ing growth factor-β1 (TGF-β1), Smad3, and phosphorylated-Smad2/3. Additionally, IPA intervention did not affect the MDA level. Attractively, the administration of IPA remodeled the gut flora structure. Conclusions: IPA aggravated CCl4-induced liver damage and fibrosis by activating HSCs via the TGF-β1/Smads signaling pathway.