AbstractThe aim of this study was to investigate the role of scoparone (SCO) in hepatic fibrosis. For this, we conducted in vivo and in vitro experiments. In vivo rats that were divided into six groups, control, carbon tetrachloride, and colchicine, as well as SCO groups, SCO50, SCO100, and SCO200 treated with 50, 100, and 200 mg/kg SCO doses, respectively. Furthermore, SCO was shown to inhibit Toll‐like receptor‐4 (TLR‐4)/nuclear factor kappa‐B (NF‐κB; TLR‐4/NF‐κB) signals by inhibiting TLR‐4, which in turn downregulates the expression of MyD88, promotes NF‐κB inhibitor‐α, NF‐κB inhibitor‐β, and NF‐κB inhibitor‐ε activation, while inhibiting NF‐κB inhibitor‐ζ. Subsequently, the decrease of phosphorylation of nuclear factor‐κB levels leads to the downregulation of the downstream inflammatory factors' tumor necrosis factor‐alpha (TNF‐α), interleukin‐6 (IL‐6), and IL‐1 beta, thus weakening hepatic fibrosis. Notably, the SCO200 treated group presented the most significant improvement. Hence, we conclude that SCO alleviates hepatic fibrosis by inhibiting TLR‐4/NF‐κB signals.