BACKGROUND: Recent reports highlighted the possibility that Yes-associated protein (YAP) and transforming growth factor-β1 (TGF-β1) can act as critical regulators of hepatic stellate cells (HSCs) activation; therefore, it is natural for compounds targeting Hippo/YAP and TGF-β1/Smad signaling pathways to be identified as potential anti-fibrotic candidates. PURPOSE: Liquiritigenin (LQ) is an aglycone of liquiritin and has been reported to protect the liver from injury. However, its effects on the Hippo/YAP and TGF-β1/Smad pathways have not been identified to date. METHODS: We conducted a series of experiments using CCl-induced fibrotic mice and cultured LX-2 cells. RESULT: LQ significantly inhibited liver fibrosis, as indicated by decreases in regions of hepatic degeneration, inflammatory cell infiltration, and the intensity of α-smooth muscle actin (α-SMA) staining in mice. Moreover, LQ blocked the TGF-β1-induced phosphorylation of Smad 3, and the transcript levels of plasminogen activator inhibitor-1 (PAI-1) and matrix metalloproteinase-2 (MMP-2) in LX-2 cells, which is similar with resveratrol and oxyresveratrol (positive controls). Furthermore, LQ increased activation of large tumor suppressor kinase 1 (LATS1) with the induction of YAP phosphorylation, thereby preventing YAP transcriptional activity and suppressing the expression of exacerbated TGF-β1/Smad signaling molecules. CONCLUSION: These results clearly show that LQ ameliorated experimental liver fibrosis by acting on the TGF-β1/Smad and Hippo/YAP pathways, indicating that LQ has the potential for effective treatment of liver fibrosis.